Review

Authors: Eli Muchtar, Hila Magen, Morie A Gertz...

Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.

Topics: Adult; Connective Tissue Diseases; Cryoglobulinemia; Cryoglobulins; Female; Hepatitis C; Humans; Leukemia, B-Cell; Lymphoma, B-Cell; Male; Middle Aged; Recurrence

PubMed: 27799164
DOI: 10.1182/blood-2016-09-719773

Review

Authors: Sigbjørn Berentsen

Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.

Topics: Anemia, Hemolytic, Autoimmune; Cryoglobulins; Hemolysis; Humans

PubMed: 32318071
DOI: 10.3389/fimmu.2020.00590

Review

Authors: Franco Dammacco, Gianfranco Lauletta, Angelo Vacca...

Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as "essential" (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications.

Topics: Humans; Antiviral Agents; Cryoglobulinemia; Hepatitis C, Chronic; Cryoglobulins; Vasculitis; Hepatitis C; Hepacivirus; Rituximab

PubMed: 35348938
DOI: 10.1007/s10238-022-00808-1

Authors: Marie Le Cann, Françoise Bouhour, Karine Viala...

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Ataxia; Autoantibodies; B-Lymphocytes; Cryoglobulins; Female; France; Hematologic Neoplasms; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Ophthalmoplegia; Paraproteinemias; Paresthesia; Retrospective Studies; Rituximab; Syndrome; Waldenstrom Macroglobulinemia

PubMed: 32959046
DOI: 10.1182/blood.2020007092

Authors: Eduardo Arellano-Rodrigo, Verónica Pons, Inmaculada Nicolau...

Topics: Adult; Cryoglobulinemia; Cryoglobulins; Female; Fibrinogens, Abnormal; Humans

PubMed: 17916105
DOI: 10.1111/j.1365-2141.2007.06823.x

Authors: D A Dotten, W Pruzanski, J Olin...

A 40-year-old woman had cryocrystalglobulinemia with IgG2(K1). To date, 27 other cases of spontaneous crystallization of a plasma protein have been reported. In all, the protein, a cryoglobulin, has been found to be an IgG molecule. The disease most commonly associated with this phenomenon has been multiple myeloma. None of the patients have had Raynaud's phenomenon, but many have had purpuric skin lesions made worse by exposure to cold. In the two cases of essential cryocrystalglobulinemia, crystals were found in the peripheral blood film. Immunologic, biochemical and ultrastructural studies have so far not demonstrated any property common to all cryocrystalglobulins.

Topics: Adult; Cryoglobulins; Crystallization; Cyclophosphamide; Female; Hematologic Diseases; Humans; Melphalan; Prednisone

PubMed: 1268777
DOI: No ID Found

Review

Authors: U Kallemuchikkal, P D Gorevic

Cryoglobulins are immunoglobulins that precipitate as serum is cooled below core body temperatures. A cryoglobulin screen is the observation of a serum specimen collected and separated while warm for cryoprecipitation over a period of up to 7 days. Values of the screening may be reported as a cryocrit, which is the volume percent of the precipitate compared with the total volume of serum. Further proof that the precipitate is indeed a cryoglobulin can be obtained by demonstrating resolubilization with warming and immunochemical analysis by immunofixation. Detailed characterization of cryoglobulins may also require rigorous washing of the precipitate, quantitation of total protein and immunoglobulins, and evaluation of serum for monoclonal gammopathy, rheumatoid factor activity, evidence of complement activation, and presence of hepatitis C virus seroreactivity or hepatitis C virus RNA. The single most important variable confounding standardization of cryoglobulin testing is the frequently improper separation of warm serum from other blood elements prior to screening and characterization.

Topics: Chemical Precipitation; Cryoglobulins; Humans; Immunoglobulins; Laboratories, Hospital; Paraproteinemias

PubMed: 10050784
DOI: 10.5858/1999-123-0119-EOC

Review

Authors: Gabriela Motyckova, Mandakolathur Murali

Cryoglobulins are immunoglobulins that precipitate below 37°C and can cause multiorgan damage. There are three types of cryoglobulins: Type I (also called simple), which is mostly associated with monoclonal gammopathy and/or other hematologic disorders and Type II and Type III (known as mixed cryoglobulins), which are associated with infectious and systemic diseases. Testing for cryoglobulins is complicated by lack of reference range, standards, and stringency in maintaining testing temperature conditions. Identification of cryoprecipitate can be critical for patient care; therefore, correct testing conditions are crucial for reliable cryoglobulin testing. The patient's blood sample should be kept at 37°C initially to avoid premature precipitation of cryoglobulins and thereby decreasing the yield for subsequent identification. This could cause a false negative result. After warm centrifugation or warm cell precipitation, the clear serum is observed at 4°C for formation of cryoprecipitate. The cryoprecipitate is then washed in cold buffer, and the resulting precipitate is warmed to 37°C and subjected to further analysis by immunodiffusion and immunofixation. In addition to Meltzer's triad of purpura, weakness and arthralgias, cryoglobulinemias have protean manifestations involving skin, joints, kidney, nervous system, as well as the hematopoietic system. The management of cryoglobulinemia especially in patients with organ damage remains difficult. Treatment of cryoglobulinemia focuses on management of the underlying lymphoproliferative disorder or infectious or systemic causes. Medical management may also include corticosteroids and other immunosuppressive agents and plasmapheresis. Rituximab therapy seems to abrogate the aberrant B cell response.

Topics: Clinical Laboratory Techniques; Cryoglobulinemia; Cryoglobulins; Disease Management; Humans; Practice Guidelines as Topic

PubMed: 21594887
DOI: 10.1002/ajh.22023

Comparative Study

Authors: F Pontet

Topics: Blood Proteins; Cryogels; Cryoglobulinemia; Cryoglobulins; Fibronectins; Humans; Hydrogels; Immunoassay; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M

PubMed: 15801150
DOI: No ID Found

Review

Authors: Cecilia Napodano, Francesca Gulli, Gian Ludovico Rapaccini...

Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.

Topics: Animals; Autoantibodies; Biomarkers; COVID-19; Chemical Precipitation; Cryoglobulinemia; Cryoglobulins; Hepatitis C; Humans; Vasculitis

PubMed: 34462057
DOI: 10.1016/bs.acc.2020.09.006