Crioglobulinemia

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).¹Manifestations vary according to type and range but the classical triad (Meltzer's triad) is purpura, weakness and arthralgias.

Classificação

Brouet's classification is:²

• 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.³

• 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 vírus da hepatite C (HCV), it has been recognised as the cause of more than 90% of MC.⁴

Type I cryoglobulinaemia presents with:

• Acrocyanosis

• 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.

• Doença renal.

• Raynaud's phenomenon.

• Neurological symptoms including paraesthesia and peripheral neuropathy.

• Dor abdominal.

• Sicca.

• Acrocyanosis.

• Hemorragia.

• 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.⁵

• More than 90% of cases of cryoglobulinaemia have a known underlying cause.

• MC is the most common dermatological extrahepatic manifestation of hepatitis C.⁴

• MC has been shown to be a negative prognostic factor of virological response to hepatitis C infection.⁶

• Hepatitis E infection also appears to be strongly associated with MC.⁷

• Síndrome do anticorpo antifosfolipídeo

• Leucemia linfocítica crônica

• Cirrose

• Glomerulonefrite

• Goodpasture's syndrome

• Síndrome hemolítico-urêmica

• Hepatite A, hepatite B ou hepatite C

• Linfoma não-Hodgkin

• Mieloma múltiplo

• Poliarterite nodosa

• Sarcoidose

• Lúpus eritematoso sistêmico (LES)

• Macroglobulinemia de Waldenström

• 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.⁸

• 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.⁵

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.⁹

Conselhos gerais

Patients should avoid cold environments.

Farmacológico

• 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.¹⁰

• Studies suggest that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.⁵

• 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.¹⁰

• Severe disease may require immunosuppressive or plasma exchange therapy.⁹

• Rituximab (monoclonal antibody against CD20-expressing B cells) has been used in refractory MCS with or without multisystem involvement.¹¹

• The course varies widely and prognosis is influenced by both cryoglobulinaemic damage to vital organs and by comorbidities associated with underlying diseases.⁵

• Mortality is higher with systemic involvement, especially when there is pulmonary haemorrhage, gastrointestinal ischemia or cardiac or central nervous system involvement.¹²

• In HCV-positive patients, baseline poor prognostic factors include the presence of severe liver fibrosis and central nervous system, kidney and heart involvement.¹³