The cryoglobulinaemias

doi:10.1016/S0140-6736(11)60242-0

The Lancet

Volume 379, Issue 9813, 28 January–3 February 2012, Pages 348-360

https://doi.org/10.1016/S0140-6736(11)60242-0 Get rights and content

Summary

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37°C and produce organ damage through two main pathways: vascular sludging (hyperviscosity syndrome, mainly in type I cryoglobulinaemia) and immune-mediated mechanisms (principally vasculitis, in mixed cryoglobulinaemia). Cryoglobulinaemia is associated with many illnesses, which can be broadly grouped into infections, autoimmune disorders, and malignancies; the most common cause is infection with hepatitis C virus. Mixed cryoglobulinaemic syndrome is diagnosed when a patient has typical organ involvement (mainly skin, kidney, or peripheral nerve) and circulating cryoglobulins. Cutaneous purpura is the most common manifestation of cryoglobulinaemic vasculitis. The most frequently affected internal organs are the peripheral nerves, kidneys, and joints. The course varies widely and prognosis is influenced by both cryoglobulinaemic damage to vital organs and by comorbidities associated with underlying diseases. More than 90% of cases of cryoglobulinaemia have a known underlying cause; therefore treatment is focused on the cause of the disorder rather than merely symptomatic relief. Studies suggest that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.

Section snippets

Definition and classification

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37°C and redissolve after rewarming. Cryoglobulinaemia refers to the presence of cryoglobulins in serum. However, the terms cryoglobulinaemic disease or cryoglobulinaemic vasculitis are used to describe patients with symptoms related to the presence of cryoglobulins. Many patients with cryoglobulinaemia remain asymptomatic.¹

The pathological nature of cryoglobulins was postulated in 1933, in a patient with

Infections

The discovery of the hepatitis C virus (HCV) in 1989⁸ radically changed the focus of research from essential to HCV-related cryoglobulinaemia.9, 10 Ferri and colleagues¹¹ confirmed the detection of circulating HCV-RNA in nearly 90% of Italian patients with mixed cryoglobulinaemia, although later studies found wide geographical variations.12, 13, 14, 15 HCV is predominantly associated with type II cryoglobulinaemia. The hepatitis B virus is reported to be associated with mixed cryoglobulinaemia.7

Epidemiology

The prevalence of cryoglobulinaemia remains unknown.³⁴ Reasons include the careful laboratory technique needed to isolate and identify cryoglobulins and the absence of a standard clinical assessment of patients with possible cryoglobulinaemia. Even so, because HCV infects more than 170 million individuals worldwide, the number of patients at risk for the complications of mixed cryoglobulinaemia is substantial.

The prevalence of HCV infection in patients with mixed cryoglobulinaemia ranges from

Generation of cryoglobulins

Cryoglobulins are generated by the clonal expansion of B cells, in the context of either lymphoproliferative disorders or persistent immune stimulation triggered by chronic infections or autoimmune diseases.5, 7, 37 Types I and II cryoglobulinaemias result from the monoclonal expansion of a clone that can be overtly malignant (multiple myeloma), smouldering (Waldenström's macroglobulinaemia, plasmacytoid lymphoma), or indolent (as in monoclonal gammopathy of unknown significance). By contrast,

Clinical manifestations

The percentage of patients with circulating cryoglobulins who develop symptoms varies from 2% to 50%.⁷ The most common presentation, the triad of purpura, arthralgia, and weakness, is reported in 80% of patients at disease onset.7, 16 The development of cryoglobulinaemic symptoms is affected by age, underlying illness (such as HCV infection) and the characteristics of the cryoglobulins (type II subclass, high serum concentrations).7, 53

Cryoglobulin testing

There are no standardised or validated diagnostic or classification criteria for cryoglobulinaemic vasculitis.⁸³ Diagnosis is based on clinical, laboratory, and histopathological data. For most patients, cryoglobulinaemic disease is diagnosed by the presence of typical organ involvement (mainly skin, kidney or peripheral nerve) and circulating cryoglobulins.

The diagnosis of cryoglobulinaemia requires demonstration of the presence of cryoglobulins in serum (panel 1). Appropriate sample

Outcome

The evolution of cryoglobulinaemic disease varies widely. Roughly half of patients have chronic disease with no involvement of vital organs. A third of patients have moderate-to-severe disease, with chronic renal failure or cirrhosis, and nearly 15% present with sudden life-threatening disease.¹⁶ Patients with cryoglobulinaemic disease have a worse 10-year survival rate compared with the rate in the general population.16, 55 Risk factors for poor outcomes include male sex, age more than 60

Conventional immunosuppression

Treatment should be modulated according to the underlying aetiopathogenesis (hyperviscosity vs vasculitis) and the severity of clinical presentation (figure 5).1, 93, 98, 105, 106 There are three broad strategies in the treatment of cryoglobulinaemia: conventional immunosuppression, antiviral treatments, and biological therapies (panel 2).

The immunosuppressive approaches used in cryoglobulinaemic vasculitis, based on high-dose glucocorticoids and cyclophosphamide, were derived mainly from

Future perspectives

A new era in our understanding of and therapeutic approach to cryoglobulinaemia began 20 years ago with the discovery of the HCV. The progressive introduction of antiviral therapies, with eradication of HCV currently regarded as the therapeutic gold standard, has improved survival rates.77, 134 However, many aspects of the disease remain unresolved.¹ The causes of essential cryoglobulinaemia are not known. Disease management remains difficult in many patients, because many do not respond or are

Search strategy and selection criteria

We searched Medline and Embase (from January, 1990, to January, 2011). We used the search term “cryoglobulinemia” in combination with “epidemiology”, “diagnosis”, “virus”, “cancer”, “autoimmune”, “pathogenesis”, “hyperviscosity”, “vasculitis”, “prognosis”, and “therapy”. We focused on publications from the past 10 years but also included commonly referenced and highly regarded older publications. We searched the reference lists of articles identified by this search strategy and selected those

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Cited by (407)

Extrahepatic manifestations of HCV where do we stand?
2024, Medicina Clinica
Hepatitis C virus (HCV) infection has been associated as up 40–70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary.
La infección por el virus hepatitis C (VHC) se ha asociado a 40-70% de los pacientes con alguna manifestación extrahepática (MEH) y 36 síndromes diferentes, atribuibles a que el VHC es linfotrópico, particularmente linfotrópico B, y no simplemente hepatotrópico. El VHC podría desencadenar alteraciones inmunológicas al ejercer un estímulo crónico del sistema inmunológico con producción de inmunoglobulinas con actividad reumatoide y formación de complejos inmunes y crioglobulinas. Estas desempeñan un papel fundamental en la mayoría de las MEH como vasculitis, glomerulonefritis, artritis y neuropatías, mientras, menos frecuentemente, el efecto citopático viral directo podría conducir a MEH independientes de crioglobulinas. El principal tratamiento de las MEH ha sido el antiviral, desde la era del interferón hasta la de los fármacos de acción directa, sin diferencias entre las dos épocas, a pesar de la mejor respuesta virológica. Son necesarias evaluaciones más prolongadas de la respuesta virológica e investigación clínica con seguimientos más largos.
Type III cryoglobulinemia associated with monoclonal gammopathy of uncertain significance and presenting with retiform purpura
2024, JAAD Case Reports
Hepatitis C and Mixed Cryoglobulinemia: An Update
2024, Infection and Autoimmunity
Vasculitides and Hepatitis C Infection
2024, Infection and Autoimmunity
Chronic infection due to hepatitis C virus (HCV) is among the most common etiologic factors of vasculitis in humans. Long-term infection is associated in less than 5% of cases with an immune-complex-mediated small-vessel vasculitis (cryoglobulinemic vasculitis – CV) or more rarely with a medium-sized vasculitis (polyarteritis nodosa-like). In recent years, significant advances have been made in our understanding of the pathogenesis, long-term prognosis, and more importantly treatment of HCV-associated CV. The newer oral direct-acting antivirals (DAAs) achieve HCV clearance in more than 95% of HCV patients (with or without cryoglobulinemia) and have transformed our therapeutic approach in patients with HCV-associated CV. Currently, all patients with CV should be treated with DAAs. Glucocorticoids, immuno-modulating or immunosuppressive agents (such as the B-cell-depleting agent rituximab), and/or plasmapheresis is added to DAAs in patients with severe or life-threatening disease manifestations. With this approach, ∼85% of patients achieve initially complete or partial clinical remission. Nevertheless, less than half of the patients show clear cryoglobulins and ∼15% demonstrate clinical relapses during long-term follow-up, despite viral clearance, indicating the need for optimization of our therapeutic approach. In this chapter, the pathogenesis, clinical features, and recent therapeutic options in HCV-associated CV and medium-sized vasculitis are presented.
Hepatitis B virus-related cryoglobulinemia: Clinical characteristics, virological features, and treatment
2023, Virus Research
Hepatitis B virus (HBV) infection is a rare etiology of cryoglobulinemia, and its clinical characteristics, virological features and treatment are poorly understood.
This retrospective study enrolled 23 patients with HBV-related cryoglobulinemia from 497 cryoglobulinemia patients at Peking Union Medical College Hospital between January 2015 and February 2023. We analyzed the clinical characteristics, virological features and management of patients with HBV-related cryoglobulinemia.
The 23 patients (13 males; median age 48 years) were all mixed cryoglobulinemia and serological HBsAg positive, while 15 patients exhibited HBV-DNA replication. The presence of HBsAg in cryoglobulins was evaluated in 7 patients, all of whom were positive. The most commonly involved organs were kidneys (69.6%), skin (65.2%), peripheral nerves (21.7%), joints (8.7%), gastrointestinal tract (4.3%), and cardiac (4.3%). Eight patients received antiviral therapy with nucleot (s)ide analogues (NAs) alone, 12 patients received NA- and corticosteroid-based regimens, and 3 patients received NA- and rituximab-based regimens based on the severity of clinical symptoms. After a median follow-up of 44 months, four patients died, and one patient was lost to follow-up. All remaining patients (n = 18) achieved clinical remission, and HBV-DNA replication was not detected in 16 out of 18 patients. There was no HBV reactivation in patients treated with rituximab. The three-year overall survival and progression-free survival were 87.0% and 80.3%, respectively.
HBV-related cryoglobulinemia patients should be treated with antiviral therapy. Corticosteroids and rituximab are effective for severe cases, but patients need to be closely monitored for therapy-related infection.
Perioperative management of cryoglobulinemia in patients requiring cardiac surgery
2023, JTCVS Techniques

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SeminarThe cryoglobulinaemias

Summary

Section snippets

Definition and classification

Infections

Epidemiology

Generation of cryoglobulins

Clinical manifestations

Cryoglobulin testing

Outcome

Conventional immunosuppression

Future perspectives

Search strategy and selection criteria

Am J Med

Am J Med

J Immunol Meth

Blood Rev

Am J Gastroenterol

Semin Arthritis Rheum

Semin Arthritis Rheum

Semin Arthritis Rheum

Gastroenterology

Hepatology

Autoimmun Rev

Dig Liver Dis

Blood

Hepatology

Blood

Lancet Infect Dis

Blood

Am J Kidney Dis

Kidney Int

Rev Neurol (Paris)

Kidney Int

Am J Med Sci

Semin Arthritis Rheum

Dig Liver Dis

Mixed cryoglobulinaemia

Orphanet J Rare Dis

Hyperproteinemia associated with multiple myeloma

Bull Johns Hopkins Hosp

Studies of cryoglobulins I: unusual purpura associated with the presence of a high concentration of cryoglobulin (cold precipitable serum globulin)

Am J Med Sci

Cryoglobulinaemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center

Medicine (Baltimore)

Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome

Science

Cryoglobulinaemia and hepatitis C virus (HCV) infection

Clin Exp Rheumatol

Antibodies to hepatitis C virus in patients with mixed cryoglobulinaemia

Arthritis Rheum

Association between hepatitis C virus and mixed cryoglobulinemia

Clin Exp Rheumatol

Hepatitis C virus infection, cryoglobulinaemia, and beyond

Rheumatology (Oxford)

Epidemiology, clinical spectrum and prognostic value of mixed cryoglobulinaemia in hepatitis C virus patients: a prospective study

Ital J Gastroenterol

Prevalence of cryoglobulins and hepatitis C virus infection in HIV-infected patients

Clin Exp Rheumatol

Mixed cryoglobulinaemia in HIV-1 infection: the role of HIV-1

Ann Intern Med

Prevalence and clinical significance of circulating cryoglobulins in HIV-positive patients with and without co-infection with hepatitis C virus

J Med Virol

Cryoglobulinaemia associated with hepatitis C virus: influence of HCV genotypes, HCV-RNA viraemia and HIV coinfection

J Viral Hepat

Prevalence of cryoglobulinaemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients

J Rheumatol

Decreased prevalence of mixed cryoglobulinaemia in the HAART era among HIV-positive, HCV-negative patients

J Med Virol

Mixed cryoglobulinaemia: new concepts

Lupus

Mixed monoclonal cryoglobulinaemia and monoclonal rheumatoid factor cross-reactive idiotypes as predictive factors for the development of lymphoma in primary Sjogren's syndrome

Arthritis Rheum

Predicting adverse outcomes in primary Sjögren's syndrome: identification of prognostic factors

Rheumatology (Oxford)

Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects

Medicine (Baltimore)

Sjögren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases

Medicine (Baltimore)

Hepatitis C virus infection in systemic lupus erythematosus: a case-control study

Seminar
The cryoglobulinaemias