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Cryoglobulins are immune complexes that precipitate at temperatures lower than 37°C and are deposited on vascular endothelium, causing vasculitis in organs such as the skin, kidneys, peripheral nerves and salivary glands. Cryoglobulins 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).Manifestations vary according to type and range but the classical triad (Meltzer's triad) is purpura, weakness and arthralgias.
Brouet's classification is:
- Type I, or simple cryoglobulinaemia: caused by monoclonal antibody - usually IgM.
- Type II and type III cryoglobulinaemia: called mixed cryoglobulinaemia (MC). They make up 75% of cryoglobulinaemias. They contain rheumatoid factor (RF), which is usually IgM. The RF is monoclonal in type II and polyclonal in type III cryoglobulinaemia.
- Type II accounts for 50-60% of cryoglobulinaemias and type III accounts for about 40-50% of cryoglobulinaemias.
- MC occurs in about 1 in 100,000 people.
- It is more common in southern Europe and usually presents between about 40 and 60 years of age, with a female-to-male preponderance of 3:1.
- Since the identification of hepatitis C virus (HCV), it has been recognised as the cause of more than 90% of MC.
Type I cryoglobulinaemia presents with:
- Retinal haemorrhage
- Severe Raynaud's phenomenon
- Arterial thrombosis
Types II and III cryoglobulinaemia produce:
- Arthralgias and arthritis in the proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, knees and ankles.
- Immune-complex glomerulonephritis.
- Vascular purpuric lesions.
- The dermatological manifestations can vary from simple cutaneous palpable purpura to complex confluent lesions, including ulcerations of the skin.
Presenting features appear in the following list in decreasing frequency:
- Cutaneous symptoms of purpura, distal necrosis, cold urticaria and ulceration.
- Joint disease.
- Renal disease.
- Raynaud's phenomenon.
- Neurological symptoms including paraesthesia and peripheral neuropathy.
- Abdominal pain.
- Arterial thrombosis.
- Facial swelling.
- Cryoglobulinaemia is associated with many illnesses, which can be broadly grouped into infections, autoimmune disorders and malignancies; the most common cause is infection with HCV.
- More than 90% of cases of cryoglobulinaemia have a known underlying cause.
- MC is the most common dermatological extrahepatic manifestation of hepatitis C.
- MC has been shown to be a negative prognostic factor of virological response to hepatitis C infection.
- Hepatitis E infection also appears to be strongly associated with MC.
- Antiphospholipid syndrome
- Chronic lymphocytic leukaemia
- Goodpasture's syndrome
- Haemolytic uraemic syndrome
- Hepatitis A, hepatitis B or hepatitis C
- Non-Hodgkin's lymphoma
- Multiple myeloma
- Polyarteritis nodosa
- Systemic lupus erythematosus (SLE)
- Waldenström's macroglobulinaemia
- Testing for cryoglobulins is complicated by lack of reference range, standards and stringency in maintaining testing temperature conditions.
- The patient's blood sample should be kept at 37°C initially to avoid premature precipitation of cryoglobulins. 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.
- Low C4 levels.
- RF: is positive in types II and III.
- Leukocytoclastic vasculitis detected by skin biopsy of recent vasculitic lesions.
- FBC: leukocytosis may occur with infection or leukaemia. There may be anaemia.
- Urinalysis may show evidence of renal disease.
- U&Es: in case of renal disease.
- LFTs: if hepatitis is indicated, check serology.
- Antinuclear antibody: if SLE is suspected.
- ESR will be elevated with rouleaux formation.
- Electrophoresis of serum and urine if there is suspicion of an underlying gammopathy.
- 90% of patients with MC will have anti-hepatitis C antibodies present.
- Mixed cryoglobulinaemic syndrome (MCS) is diagnosed when a patient has typical organ involvement (mainly skin, kidney or peripheral nerve) and circulating cryoglobulins.
Further tests - if other diseases are suspected.
Treatment is usually focused on the cause of the associated condition rather than merely symptomatic relief. The management often involves dealing with very different clinical patterns, activity and severity with the aim of preventing irreversible organ damage, reducing pain and improving the patient's quality of life.
Patients should avoid cold environments.
- The aim is to limit precipitation of cryoglobulin and the inflammation that results.
- Non-steroidal anti-inflammatory drugs (NSAIDs) can be useful for arthralgia and fatigue.
- Immunosuppressive agents such as corticosteroids and/or cyclophosphamide or azathioprine can be used when there is evidence of organ involvement such as vasculitis, renal disease, progressive neurological features or severe skin disease.
- However, there is concern regarding the potential adverse effects that immunosuppressive therapy with glucocorticoids and cytotoxic drugs could have on an underlying chronic viral infection.
- Studies suggest that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.
- MC due to HCV (HCV-MC) is often treated with standard anti‐HCV therapy plus ribavirin.
- Immunosuppressive agents are typically reserved for HCV-MC patients with severe disease manifestations, such as membranoproliferative glomerulonephritis, severe neuropathy and life-threatening complications.
- Severe disease may require immunosuppressive or plasma exchange therapy.
- Rituximab (monoclonal antibody against CD20-expressing B cells) has been used in refractory MCS with or without multisystem involvement.
- The course varies widely and prognosis is influenced by both cryoglobulinaemic damage to vital organs and by comorbidities associated with underlying diseases.
- Mortality is higher with systemic involvement, especially when there is pulmonary haemorrhage, gastrointestinal ischemia or cardiac or central nervous system involvement.
- In HCV-positive patients, baseline poor prognostic factors include the presence of severe liver fibrosis and central nervous system, kidney and heart involvement.
Further reading and references
Ghetie D, Mehraban N, Sibley CH; Cold hard facts of cryoglobulinemia: updates on clinical features and treatment advances. Rheum Dis Clin North Am. 201541(1):93-108, viii-ix. doi: 10.1016/j.rdc.2014.09.008.
Brouet JC, Clauvel JP, Danon F, et al; Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974 Nov57(5):775-88.
Terrier B, Cacoub P; Cryoglobulinemia vasculitis: an update. Curr Opin Rheumatol. 2013 Jan25(1):10-8. doi: 10.1097/BOR.0b013e32835b15f7.
Dedania B, Wu GY; Dermatologic Extrahepatic Manifestations of Hepatitis C. J Clin Transl Hepatol. 2015 Jun 283(2):127-33. doi: 10.14218/JCTH.2015.00010. Epub 2015 Jun 15.
Ramos-Casals M, Stone JH, Cid MC, et al; The cryoglobulinaemias. Lancet. 2012 Jan 28379(9813):348-60. doi: 10.1016/S0140-6736(11)60242-0. Epub 2011 Aug 23.
Gragnani L, Fognani E, Piluso A, et al; Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study. Hepatology. 2015 Apr61(4):1145-53. doi: 10.1002/hep.27623. Epub 2015 Feb 10.
Bazerbachi F, Haffar S, Garg SK, et al; Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive review of the literature. Gastroenterol Rep (Oxf). 2015 Sep 10. pii: gov042.
Motyckova G, Murali M; Laboratory testing for cryoglobulins. Am J Hematol. 2011 Jun86(6):500-2. doi: 10.1002/ajh.22023.
Scarpato S, Atzeni F, Sarzi-Puttini P, et al; Pain management in cryoglobulinaemic syndrome. Best Pract Res Clin Rheumatol. 2015 Feb29(1):77-89. doi: 10.1016/j.berh.2015.04.033. Epub 2015 Jun 8.
Saadoun D, Resche Rigon M, Thibault V, et al; Peg-IFNalpha/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis. 2014 May73(5):831-7. doi: 10.1136/annrheumdis-2012-202770. Epub 2013 Apr 20.
Visentini M, Tinelli C, Colantuono S, et al; Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review. Autoimmun Rev. 2015 Oct14(10):889-96. doi: 10.1016/j.autrev.2015.05.013. Epub 2015 May 29.
Terrier B, Semoun O, Saadoun D, et al; Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis. Arthritis Rheum. 2011 Jun63(6):1748-57. doi: 10.1002/art.30319.
Cacoub P, Comarmond C, Domont F, et al; Cryoglobulinemia Vasculitis. Am J Med. 2015 Sep128(9):950-5. doi: 10.1016/j.amjmed.2015.02.017. Epub 2015 Mar 30.