I. What every physician needs to know.
Cryoglobulins (CG) are immunoglobulin (Ig) complexes that precipitate from the serum at blood temperatures below 37°C and redissolve on rewarming. Cryoglobulinemia refers to a condition with circulating cryoglobulins in the serum. Cryoglobulinemic vasculitis refers to the small to medium vessel vasculitis resulting from the CG-containing immune complexes. It should be noted that cryoglobulins are distinct from cryofibrinogen which results from cryoprecipitation of frozen plasma and consists of fibrin, fibrinogen, fibronectin and fibrin split products.
There are several classifications, but the most commonly cited one is the Brouet classifications (which describes three basic types based on the clonality and types of immunoglobulins, particularly with regard to rheumatoid factor [RF] binding activity):
Type I (monoclonal) – isolated monoclonal lg (typically IgG or IgM, and less commonly lgA or free light chains), and found in conditions like multiple myeloma and Waldenstrom’s macroglobulinemia. It accounts for 10-15% of all cryoglobulinemias.
Type II (mixed) – mixture of monoclonal IgMs and polyclonal IgGs, with the IgM component having positive RF activity. Also called essential mixed cryoglobulinemia, this type is mostly found in patients with chronic hepatitis C and HIV infections. This is the most common type and accounts for 40-60% of all cryoglobulinemias.
Type III (mixed, polyclonal) – mixed cryoglobulinemias consisting of polyclonal IgG and polyclonal IgMs. Also a common type, mostly in association with connective tissue diseases, accounting for 25-30% of all cryoglobulinemias.
In fact, both type II and type III are referred to as mixed cryoglobulinemia since they both consist of mixture of IgMs and IgGs.
Cryoglobulinemias are associated with a variety of illnesses (listed below), three most common categories being: infections, autoimmune disorders, and malignancies. Hepatitis C virus (HCV) infection is by far the most common condition associated with cryoglobulinemia.
Infections (type II and type III): viral (HCV, human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis A virus, Epstein-Barr Virus, cytomegalovirus); bacterial (endocarditis, Lyme, syphilis); Fungal (coccidioidomycosis); parasitic (malaria, schistosomiasis)
Autoimmune (type III, type II): systemic lupus erythematosus, Sjogren’s syndrome, polyarteritis nodosa, rheumatoid arthritis, inflammatory bowel diseases, Sarcoidosis
Hematological (type I): Multiple myeloma, Waldenstrom’s macroglobulinemia, Non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, thrombotic thrombocytopenic purpura, myelodysplastic syndrome
Renal transplant recipients
Idiopathic/essential (10% over all, 25% HCV-negative patients)
Medications: cocaine, interferon alpha
Others: alcoholic cirrhosis
Hepatitis C and cryoglobulinemia
HCV infection is by far the most common condition associated with mixed cryoglobulinemia. Almost half of patients with chronic hepatitis C have mixed cryoglobulinemia. Similarly, majority (up to 90% in Mediterranian population) of patients with essential mixed cryoglobulinemia (type II or III) have evidence of HCV infection. Therefore all patients with type II or type III cryoglobulinemias should be screened for HCV infection. Conversely, HCV patients with progressive and worsening renal function or cutaneous involvement should be tested for cryoglobulinemia.
Diagnosis of HCV in patients with cryoglobulinemia can be difficult because HCV seromarkers may be undetectable in such patients. This can occur if the anti-HCV antibody and the HCV RNA concentrate in the cryoprecipitate. Therefore, if the serum is negative for anti-HCV antibody or HCV RNA, and there is still high suspicion for HCV, the cryoprecipitate should be tested for anti-HCV antibody or HCV RNA.
The exact mechanism by which HCV leads to essential mixed cryoglobulinemia is not clear. One possible explanation is ability of HCV to bind with B lymphocytes via the CD 81 cell surface receptor. It thereby potentially lowers the activation threshold of B lymphocytes, lead to B-cell clonal expansion, overproduction of immunoglobulins and ultimately formation of cryoglobulins (by mechanisms not clearly understood yet).
II. Diagnostic Confirmation: Are you sure your patient has Cryoglobulinemia?
Diagnosis of cryoglobulinemia typically requires demonstration of cryoglobulinemia (positive cryoglobulins in serum) in the presence of typical organ involvement (skin, kidney or peripheral nerve).
Appropriate sample collection and handling is crucial since false negative results are common with improper sample collection or handling (see below in lab testing).
There are no validated diagnostic criteria but some have been proposed, based on combination of clinical, serological and histopathological data. Histopathological examination is not always necessary, however.
Hallmark of the disease include palpable purpura, circulating mixed cryoglobulins and low C4, and leukocytoclastic vasculitis involving medium or small vessels of the affected tissue.
Biopsy of the affected organs (usually the skin, kidneys or peripheral nerve) can be done to confirm the diagnosis in the affected organ. The typical findings in biopsy include leukocytoclastic vasculitis (cutaneous lesions), membranoproliferative glomerulonephritis (kidneys) and axonal degeneration and demyelination (peripheral nerves).
A. History Part I: Pattern Recognition:
Type I cryoglobulinemia predominantly affects the skin, kidney and bone marrow where as type II and III predominantly involves the skin, peripheral nervous system and kidney.
Type I cryoglobulinemias usually present with hyperviscosity syndromerather than vasculitis, and generally lack the general/constitutional symptoms. Hyperviscosity syndrome may manifest as: headache, visual symptoms, purpura, livedo reticularis, Raynaud’s phenomenon, digital ischemia and rarely distal gangrene.
Type II and type III (mixed type) cryoglobulinemias usually present with constitutional and non-specific symptoms, such as arthralgias, fatigue and myalgias, as well as palpable purpura, cutaneous vasculitis (cryoglobulinemic vasculitis) and peripheral neuropathy. But this classical “Meltzer’s triad” of purpura, arthralgias and weakness is seen only in 25-30% of patients. Manifestations often wax and wane over time, with spontaneous remissions and exacerbations.
Systemic symptoms are usually due to type II or type III cryoglobulinemias and may include:
Constitutional: low grade fever, weakness
Dermatological (54-82%): purpura (lower extremity), livedo reticularis, leg ulcers, Raynaud’s, leucocytoclastic vasculitis
Rheumatological (44-71%): arthralgia (symmetric, migratory, small and medium joints)
Renal (50%): glomerulonephritis (proteinuria, hematuria, hypertension, edema, acute renal failure)
Neurological (17-60%): peripheral neuropathy, mononeuritis multiplex
Hematological: anemia, thrombocytopenia
Pulmonary (<5%): usually subclinical, such as dyspnea, cough, pleurisy pulmonary hemorrhages, pulmonary vasculitis, etc.
Gastrointestinal (GI) (2-6%): intestinal ischemia, abdominal pain, hepatosplenomegaly, abnormal liver enzymes
B. History Part 2: Prevalence:
The prevalence of clinically significant cryoglobulinemia is estimated to be about 1:100,000; more common in females (3:1 female to male ratio) and usually detected around the 6th decade of life. Significant proportions of patients with HCV, HIV, and connective tissue disorders will have detectable levels of CGs in their serum (about 40-65% of HCV infection, 15-20% of HIV infection, 15-25% of connective tissue diseases).
C. History Part 3: Competing diagnoses that can mimic disease cryoglobulinemia.
Since cryoglobulinemia can manifest clinically with two distinct patterns, their differential diagnosis also are distinct.
Cryoglobulinemic vasculitis (type II and III):
1) Other vasculitides that affect small or medium-sized vessels:
Drug-induced small vessel vasculitis (hypersensitivity vasculitis)
ANCA-associated vasculitis (e.g., granulomatosis with polyangiitis [formerly Wegener’s], microscopic polyangiitis, Churg Strauss syndrome)
Infection related vasculitis (e.g., bacterial endocarditis, poststreptococcal vasculitis and glomerulonephritis)
Vasculitis associated with a connective tissue disorder (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome)
2) Disorders that mimic the symptoms and findings of vasculitis, including:
Infectious (e.g., Rickettsial infections, malaria, Babesiosis)
Thrombotic and embolic disorders (e.g., antiphospholipid syndrome, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, atrial myxoma)
Cryoglobulinemic hyperviscosity syndrome (type I)
Proliferative: polyclonal/monoclonal gammopathy (Waldenstrom hyperglobulinemic purpura, Waldenstrom macroglobulinemia)
Infections: malaria, babessiosis
Hematological: leukostasis, polycythemia, Sickle cell disease
D. Physical Examination Findings.
The classical presentation is “Meltzer’s triad” of palpable purpura, arthralgias and weakness (present in 25-30% and up to 80% at the disease onset).
The classic purpura usually occurs as petechial lesions in the legs and can extend to abdomen, but rarely to upper extremities. Bullous and vesicular lesions are uncommon.
Arthralgias usually involving joints of hand, wrists and knees without signs of inflammation. X- rays will show no evidence of bone erosion.
Weakness and fatigue are subjective. Sensory symptoms such as paresthesia precede motor weakness. EMG will show polyneuropathy more common that mononeuritis multiplex.
Other findings may include:
Digital ischemia and necrosis
E. What diagnostic tests should be performed?
Serological tests for cryoglobulins (to document circulating cryoglobulins)
Laboratory tests (to evaluate the effect on organs involved and to identify etiological factors)
Biopsy of the affected organs (usually the skin, kidneys or peripheral nerve, to confirm the diagnosis in the affected organ)
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Following are the basic labs that should be ordered in evaluation for possible cryoglobulinemia:
1) Testing for cryoglobulins:
To prevent false negative results, appropriate sample collection and handling is crucial. 10-20mL of blood is drawn into syringes and collection tubes that have been pre-warmed to 37ºC without anticoagulants. Blood samples should be kept warm to 37º-40ºC at all times during collection, transport, clotting and centrifugation. The serum is then placed in a graduated (Wintrobe) tube and refrigerated (4ºC) to allow the precipitation of CG. In type I cryoglobulinemia, precipitates are often seen within 24 hours (sometimes in less than 90 minutes), but it may take 3-5 days for the complete precipitation, especially of the mixed CGs. A cryocrit is then determined by measuring the packed (centrifuged) volume of the precipitate as a percentage of the original serum volume at 4ºC.
False negative results of laboratory testing may result from mishandling of the specimen. Cooling below 37ºC during collection, clotting or centrifugation may cause the CGs to be removed from the serum. Thus, when cryoglobulinemia is suspected clinically, a negative result from routine laboratory testing for CGs does not eliminate the possibility of CG-mediated disease. On the other hand, many infections may present with transient low levels of mixed polyclonal cryoglobulunemia. Hence, expert laboratory interpretation based on the clinical context is important.
Cryoglobulin concentration can be assayed indirectly by measuring total protein concentration within the cryoprecipitate or directly by estimation of cryocrit. Quantification of cryocrit is useful in monitoring response to treatment, particularly in hyperviscosity syndromes.
Cryoglobulin subtype can be identified directly by immunofixation of the redissolved cryoprecipitate, or indirectly by serum immunofixation.
2) Other laboratory tests:
Several serological and biochemical tests are useful in evaluating the effects of organ involvement and in identifying etiological factors and are important part of the work up:
Complete blood count with differential
Liver function tests
Erythrocyte sedimentation rate
Serum protein electrophoresis
Complements (C3, C4, CH50)
HCV RNA/anti-HCV, HBV and HIV serology
Autoantibodies (anti-dsDNA, anti- Ro/La, anti-citrullinated abs)
Serum viscosity (in hyperviscosity syndrome)
The following are supportive of the diagnosis of cryoglobulinemia:
False elevation of white blood cells or platelets (due to cryoprecipitation on an automated counter)
Complements: low C4 and CH50 levels, variable C3 levels
Elevated erythrocyte sedimentation rate and C- reactive protein
HCV RNA (positive in 80% of time, anti-HCV antibody may be negative)
Positive ANA and other autoantibodies
3) Biopsy of affected tissue (skin, kidney, peripheral nerve)
Biopsy of the affected organ (e.g., skin, kidney, peripheral nerve) is not essential, but may be necessary to confirm presence of the disease in the affected organ. The typical histopathological findings include leukocytoclastic vasculitis (cutaneous lesions), membranoproliferative glomerulonephritis (kidneys) and axonal degeneration and demyelination (peripheral nerves).
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
No imaging test is needed for diagnosis of cryoglobulinemia. Plain X-ray films of the involved joints may be obtained, but in arthralgia due to cryoglobulinemia, X-rays show normal findings with no evidence of bone erosions or inflammation. Chest X-ray may be often useful to differentiate from other etiologies. Ultrasound of the liver may be helpful in identifying underlying liver disorder.
III. Default Management.
Treatment is challenging and should be directed to the underlying cause of cryoglobulinemia whenever possible. The majority of patients with mild and slowly progressive disease will usually do well and no therapy is recommended. Available treatment options include: conventional immunosuppresssive therapy, antiviral therapy (against HCV), apheresis (e.g., for hyperviscosity syndrome), and biological therapies which can be utilized in patients with progressive systemic symptoms or complications.
There is no evidence base regarding the role of immunosuppressive therapy in treatment of cryoglobulinemia per se. The treatment strategies are derived from the experiences of treating other systemic vasculitides. Prednisone and cyclophosphamide are the mainstay of therapy for slowly progressive cryoglobulinemias and may be beneficial in terms of stabilization of renal functions but there are no controlled studies to demonstrate it. Immunosppression with high dose steroids and/or immunosuppressive agents (such as cyclophosphamide, mycophenolate mofetil, azathioprine) are usually utilized in patients with severe cryoglobulinemic vasculitis or life-threatening complications such as acute and worsening renal failure, digital gangrene, GI or pulmonary involvement, etc.
The goal of such therapy should be to discontinue conventional immunosuppressive agents within 2-3 months, once the major end-organ effects have been controlled. High dose prednisone and cyclophosphamide are usually used to control the severe vasculitis in the acute setting, and agents like mycophenolate mofetil, azathioprine are used for remission maintenance.
Potential downside of aggressive immunosuppressive therapy includes progression of HCV, and possible exacerbation of low grade non-Hodgkin’s lymphoma.
All patients in immunosuppressive therapy will require close clinical monitoring of blood counts, liver and renal functions, surveillance for the development of opportunistic infections, and should receive prophylaxis for pneumocystis pneumonia.
Plasma exchange and plasmapheresis
Plasma exchange and plasmapheresis (removal of CGs from the circulation) are the mainstay of therapy for hyperviscosity syndrome. These can also be useful for acute severe diseases such as progressive renal failure, distal gangrene or advanced neuropathy.
Apheresis, however, does not treat the underlying disease and can lead to rebound increase in cryoglobulin production following cessation of therapy. A short course of cyclophosphamide (up to 6 weeks) may be useful to prevent such rebound.
B-cell depletion with rituximab is one of the most promising biological approach in the treatment of cryoglobulinemia. A few recent clinical trials among HCV patients with cryoglobulinemia have shown a strong benefit of adding rituximab to the standard of care (pegylated interferon-alpha plus ribavirin) with shorter mean time to clinical remission, better renal response rate, and higher cryoglobulin clearance.
Role of rituximab in cryoglobulinemia from other etiology remains to be evaluated. Other potential biological agents in the horizon include Toll-like receptor agonists and anti-tumor-necosis factor agents but none is available for clinical use yet.
Antiviral therapy against HCV is the mainstay of treatment for cryoglobulinemic disorders associated with HCV infection. There is good evidence that treatment leads to reduction and even disappearance of CGs, improve on cutaneous vasculitis and rashes, and improvement of arthralgia and arthritis. Therefore, antiviral treatment should be considered in all HCV patients with cryoglobulinemia even if there is no significant liver disease to warrant treatment otherwise. However, there is no definite improvement on kidney functions or polyneuropathy and recurrence can occur within months after discontinuation of therapy. Of note, interferon treatment can lead to exacerbation of vasculitis or worsening of renal function. Fortunately, several classes of highly effective and safe direct-acting oral antiviral agents have recently been made available, and have essentially eliminated the need for interferon or ribavirin as the mainstay of HCV therapy. Readers are highly recommended to refer to hcvguidelines.org where HCV treatment guidelines are constantly updated as the new evidences are coming in a very accelerated pace.
In general, patients with cryoglobulinemia and mild to moderate proteinuria and slowly progressive kidney disease can be treated with standard antiviral regimens. While most of the newly developed oral antiviral agents are safe and effective, certain agents which are renally cleared (ribarin and sofosbuvir in particular) are contraindicated in the presence of advanced renal impairment with estimated GFR of <30 ml/sec. Patients with marked proteinuria with evidence of progressive kidney disease or an acute flare of cryoglobulinemia can be first treated with rituximab, cyclophosphamide plus methylprednisolone, or plasma exchange followed by antiviral therapy once the acute process has subsided.
Immunosuppressive therapy is generally avoided in HCV-related cryoglobulinemia for fear of HCV disease flare; however, this may be essential to control severe disease quickly or to alter the course of a rapidly progressive disease, as a bridge to subsequent antiviral or biological therapy. Alternatively, plasmapheresis can be tried. Antiviral therapy should be delayed for two to four months in patients with severe disease who are initially treated with plasmapheresis or immunosuppressive therapy.
Those patients who progress to end-stage renal disease are treated with dialysis or renal transplantation. Renal transplantation has been successfully performed in mixed cryoglobulinemia.
Patients who have cryoglobulinemia associated with hepatitis B infection may go into remission with anti-HBV therapy with lamivudine or entecavir.
IV. Management with Co-Morbidities
A. Renal Insufficiency.
Ribavirin is contraindicated and pegylated interferons are better avoided in patients with creatinine clearance of less than 50 mg/min. Likewise, sofosbuvir is to be avoided in patients with severe renal impairment with creatinine clearance of less than 30 mg/min. Dose adjustments should be done according to FDA recommendations or package inserts of individual agents.
B. Liver Insufficiency.
Interferon based therapy is generally contraindicated in patients with decompensated cirrhosis. While most oral antiviral agents are safe and well-tolerated, protease inhibitors are generally avoided in patients with advanced cirrhosis. Patients receiving immunosuppressive therapy should have their liver functions checked at least every 3-4 months, and more frequently in the initial treatment phase.
What’s the evidence?
Ramos-Casals, M, Stone, JH, Cid, MC, Bosch, X. “The cryoglobulinemias”. Lancet. vol. 379. 2012. pp. 348
De Vita, S, Soldano, F, Isola, M. “Preliminary classification criteria for the cryoglobulinaemic vasculitis”. Ann Rheum Dis. vol. 70. 2011. pp. 1183
Sansonno, D, Dammacco, F. “Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations”. Lancet Infect Dis. vol. 5. 2005. pp. 227
Saadoun, D, Resche-Rigon, M, Sene, D. “Rituximab plus PEG-interferon alpha/ribavirin compared to PEG-interferon alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia”. Blood. vol. 116. 2010. pp. 326
Dammacco, F, Tucci, FA, Lauletta, G. “Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study”. Blood. vol. 116. 2010. pp. 343
Saadoun, D, Resche Rigon, M, Thibault, V. “Peg-IFNα/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24”. Ann Rheum Dis. 2013 Apr 20.
Cacoub, P, Terrier, B, Saadoun, D. “Hepatitis C virus-induced vasculitis: therapeutic options”. Ann Rheum Dis. vol. 73. 2014. pp. 24
“AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C”.
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Cryoglobulinemia?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic disease cryoglobulinemia.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- III. Default Management.
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.