Cryoglobulinemia

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Cryoglobulinemia

BASICS

DESCRIPTION

Prevent or manage progression of underlying disease, if applicable. ГЎ

Initial Tests (lab, imaging)

Check the main organ systems involved: ГЎ

Specific CG treatment regimens are largely empiric due to lack of long-term multicenter, randomized, controlled trials, although consensus guidelines suggest the following: ГЎ

Mixed CG: Low-antigen content (LAC) diet is suggested for symptomatic improvement (no meat except turkey; no eggs, dairy products, or food additives; no preservatives; no beverages except water; diet is mostly fruits and vegetables). The hypothesized mechanism is a reduction in antigen input load for the reticuloendothelial system which allows that system to more efficiently process circulating immune complexes. ГЎ

Vasculitis Foundation: http://www.vasculitisfoundation.org/ ГЎ

11 Krishnamurthy ГЎK, Mohapatra ГЎS, Mishra ГЎTK, et al. Early onset mixed cryoglobulinemia in hepatitis C. Indian J Pathol Microbiol. 2015;58(3):381-383.22 Takada ГЎS, Shimizu ГЎT, Hadano ГЎY, et al. Cryoglobulinemia (review). Mol Med Rep. 2012;6(1):3-8.33 Porres-Aguilar ГЎM, Rodriguez-Castro ГЎCE, Osvaldo ГЎP, et al. Finger necrosis due to cryoglobulinemic vasculitis in association with membranous nephropathy. Proc (Bayl Univ Med Cent). 2015;28(1):72-74.44 Owen ГЎRG, Treon ГЎSP, Al-Katib ГЎA, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia. Semin Oncol. 2003;30(2):110-115.55 Giuggioli ГЎD, Manfredi ГЎA, Colaci ГЎM, et al. Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of literature. Autoimmun Rev. 2013;12(11):1058-1063.66 Sunderk Г‚tter ГЎC, Pappelbaum ГЎKI, Ehrchen ГЎJ. Cutaneous symptoms of various vasculitides [in German]. Hautarzt. 2015;66(8):589-598.77 Pietrogrande ГЎM, De Vita ГЎS, Zignego ГЎAL, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev. 2011;10(8):444-454.88 Terrier ГЎB, Krastinova ГЎE, Marie ГЎI, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119(25):5996-6004.99 Quartuccio ГЎL, Zuliani ГЎF, Corazza ГЎL, et al. Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: long-term follow up data of a randomized controlled multicentre study. J Autoimmun. 2015;63:88-93.

273.2 Other paraproteinemias ГЎ

Cryoglobulins (CGs) consists of immunoglobulins (Igs) and complement precipitating in serum and plasma.
CGs precipitate at cold temperatures 98.6 в–‘F (<37 в–‘C) and dissolve on rewarming.
Clinical symptoms are often secondary to either small vessel occlusion and a hyperviscosity syndrome in type I CGs or the formation of CG-containing immune complexes leading to vasculitis in type II and type III CGs.
Brouet classification categorizes CGs by clonality and rheumatoid factor (anti-IgG) activity:Type IMonoclonal Ig; IgM is most common.Less frequently IgG, IgA, free Ig light chainsType IIMonoclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal IgMonoclonal fraction is rarely IgG or IgA.Type IIIPolyclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig (1)

Type IMonoclonal Ig; IgM is most common.Less frequently IgG, IgA, free Ig light chains
Type IIMonoclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal IgMonoclonal fraction is rarely IgG or IgA.
Type IIIPolyclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig (1)

Monoclonal Ig; IgM is most common.
Less frequently IgG, IgA, free Ig light chains

Monoclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig
Monoclonal fraction is rarely IgG or IgA.

Polyclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig (1)

EPIDEMIOLOGY

Healthy patients may have low concentrations of CGs present in the serum (<0.06 g/L).
Clinically relevant cryoglobulinemia is far more common in patients with chronic infections or inflammation.

Distribution (percentage of all cases) of CG:Type I CG: 10-15%Type II CG: 50-60%Type III CG: 30-40%

Type I CG: 10-15%
Type II CG: 50-60%
Type III CG: 30-40%

Mixed CG (CGs type II and type III) is female (1:100,000) > male: (3:1); onset in 6th decade
Heterogenous geographic distribution: highest incidence in areas with increased hepatitis C virus (HCV) infection (2)[B]

ETIOLOGY AND PATHOPHYSIOLOGY

Exact mechanism of cold insolubility in these cryoproteins is unknown. Hypotheses include reduced concentrations of sialic acid and galactose in the Fc region of Ig as well as steric conformation changes due to temperature variation.
Type IAn underlying lymphoproliferative disorder causes monoclonal B-cell proliferation.B cells produce CG, which precipitates, causing hyperviscosity and vessel damage.
Types II and IIIB-cell hyperactivation or hyperproliferation (from HCV or another chronic inflammatory state) produce Ig with rheumatoid factor activity, which leads to immune complex formation.Immune complex deposition and subsequent complement activation causes small vessel damage.HCV correlationHCV displays lymphotropism. The E2 capsid protein of HCV binds site to CD81, a site present on hepatocytes, T lymphocytes, and B lymphocytes.Patients infected with HCV who have mixed cryoglobulinemia (MC) have been found to have higher viral loads than patients with HCV and no MC.
Disease manifestations of CG may arise due to the following causes:Chronic immune stimulation or lymphoproliferation resulting in the increased production of CGs (3)[A]Immune complex formation among CGs with antigensInsufficient clearance of CGs and their immune complexesConsider small vessel vasculitis: may present with necrosis at cold exposed areas (4)[A]

An underlying lymphoproliferative disorder causes monoclonal B-cell proliferation.
B cells produce CG, which precipitates, causing hyperviscosity and vessel damage.

B-cell hyperactivation or hyperproliferation (from HCV or another chronic inflammatory state) produce Ig with rheumatoid factor activity, which leads to immune complex formation.
Immune complex deposition and subsequent complement activation causes small vessel damage.
HCV correlationHCV displays lymphotropism. The E2 capsid protein of HCV binds site to CD81, a site present on hepatocytes, T lymphocytes, and B lymphocytes.Patients infected with HCV who have mixed cryoglobulinemia (MC) have been found to have higher viral loads than patients with HCV and no MC.

HCV displays lymphotropism. The E2 capsid protein of HCV binds site to CD81, a site present on hepatocytes, T lymphocytes, and B lymphocytes.
Patients infected with HCV who have mixed cryoglobulinemia (MC) have been found to have higher viral loads than patients with HCV and no MC.

Chronic immune stimulation or lymphoproliferation resulting in the increased production of CGs (3)[A]
Immune complex formation among CGs with antigens
Insufficient clearance of CGs and their immune complexes
Consider small vessel vasculitis: may present with necrosis at cold exposed areas (4)[A]

RISK FACTORS

Hematologic/lymphoproliferative diseases (type I CG)
HCV infection (type II CG > type III CG), other chronic infections (mixed CG)

GENERAL PREVENTION

COMMONLY ASSOCIATED CONDITIONS

Infections:Viral (commonly hepatitis C, hepatitis B, HIV), bacterial, fungal, parasitic (rare)
Hematologic/lymphoproliferative diseases:Non-Hodgkin/Hodgkin lymphomaChronic leukemiaMultiple myelomaWaldenstr Г‚m macroglobulinemia
Autoimmune/chronic inflammatory diseases:Sj Г‚gren syndromeSystemic lupus erythematosusRheumatoid arthritisInflammatory bowel disease (IBD) (5)[C]

Viral (commonly hepatitis C, hepatitis B, HIV), bacterial, fungal, parasitic (rare)

Non-Hodgkin/Hodgkin lymphoma
Chronic leukemia
Multiple myeloma
Waldenstr Г‚m macroglobulinemia

Sj Г‚gren syndrome
Systemic lupus erythematosus
Rheumatoid arthritis
Inflammatory bowel disease (IBD) (5)[C]

DIAGNOSIS

Type ICommonly asymptomaticMore frequent association with signs of peripheral vessel occlusion (e.g., Raynaud phenomenon, acrocyanosis, livedo reticularis, purpura, ulcers, gangrene), less with signs of vasculitis
Types II and III: mixed cryoglobulinemia syndromeCaused by immune complex-mediated vasculitisCharacterized by Meltzer triadPurpuraWeaknessArthralgiasMultiple organ involvement is common:Cutaneous vasculitis, purpura, with/without necrosis (3)[B]Membranoproliferative glomerulonephritis (nephropathy)Peripheral neuropathy

Commonly asymptomatic
More frequent association with signs of peripheral vessel occlusion (e.g., Raynaud phenomenon, acrocyanosis, livedo reticularis, purpura, ulcers, gangrene), less with signs of vasculitis

Caused by immune complex-mediated vasculitis
Characterized by Meltzer triadPurpuraWeaknessArthralgias
Multiple organ involvement is common:Cutaneous vasculitis, purpura, with/without necrosis (3)[B]Membranoproliferative glomerulonephritis (nephropathy)Peripheral neuropathy

Purpura
Weakness
Arthralgias

Cutaneous vasculitis, purpura, with/without necrosis (3)[B]
Membranoproliferative glomerulonephritis (nephropathy)
Peripheral neuropathy

HISTORY

Constitutional/nonspecific: fever, myalgias, arthralgia, malaise, generalized weakness, sensory changes
Hyperviscosity: blurring of vision, headache, vertigo, dizziness, diplopia, ataxia, confusion, dementia, stroke
Vasculitis: peripheral neuropathy, palpable purpura, other end-organ involvement (e.g., kidneys, liver)
Past medical history: risk factors for hepatitis C, lymphoproliferative disorders

PHYSICAL EXAM

Skin: purpura (intermittent, nonblanching, palpable, beginning in legs), ulcers, Raynaud phenomenon, livedo reticularis, acrocyanosis
GI: hepatomegaly
Lymph: lymphadenopathy, splenomegaly
Extremities: synovitis, signs of peripheral vascular occlusion
Neurologic: peripheral neuropathy

DIFFERENTIAL DIAGNOSIS

Possible causes of small vessel vasculitis: Henoch-Sch Г‚nlein purpura, lupus vasculitis, rheumatoid vasculitis, Sj Г‚gren syndrome vasculitis, hypocomplementemic urticarial vasculitis, Beh Еѕet syndrome, Goodpasture syndrome, serum sickness vasculitis, drug-induced immune complex vasculitis, infection-induced immune complex vasculitis, antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitis, paraneoplastic syndrome-associated vasculitis, IBD-associated vasculitis
Possible causes of hyperviscosity: Waldenstr Г‚m macroglobulinemia, polycythemia, sickle cell anemia, malaria, babesiosis (6)

DIAGNOSTIC TESTS & INTERPRETATION

GeneralCBC with peripheral smearElectrolytesLiver function tests (LFTs)Hepatitis B and C serologyBUN, creatinineUrinalysisRheumatoid factorESRC-reactive protein
SpecificSerologic test for CGs (blood collection and initial storage needs to be at 98.6 в–‘F [37 в–‘C]); following detection of CGs, further testing including electrophoresis and immunofixation should be completed.Serum complement levels (low C4, normal or slightly decreased C3)Rheumatologic (e.g., antinuclear antibody, ANCA)

CBC with peripheral smear
Electrolytes
Liver function tests (LFTs)
Hepatitis B and C serology
BUN, creatinine
Urinalysis
Rheumatoid factor
ESR
C-reactive protein

Serologic test for CGs (blood collection and initial storage needs to be at 98.6 в–‘F [37 в–‘C]); following detection of CGs, further testing including electrophoresis and immunofixation should be completed.
Serum complement levels (low C4, normal or slightly decreased C3)
Rheumatologic (e.g., antinuclear antibody, ANCA)

Kidneys: proteinuria, microscopic hematuria, and arterial hypertension common at diagnosis
Nervous system: peripheral neuropathy in type II CG and type III CG
Liver: normal or increased liver enzymes, steatosis, chronic hepatitis, cirrhosis

Renal biopsy: Most common type of nephropathy is membranoproliferative glomerulonephritis.
Bone marrow: may be indicated for type I cryoglobulinemia; examination often reveals underlying hematologic condition.
Liver biopsy: investigation for underlying hepatitis
Skin biopsy: leukocytoclastic vasculitis

TREATMENT

Goals:Symptomatic management of vasculitis and/or hyperviscosity and limit damage caused by circulating immune complexesLimit or suppress B-lymphocyte proliferation.Eradicate HCV (if applicable, CGs types II and III) (2)[C].
General measures:Most important to treat underlying diseaseAsymptomatic: Observe.Mild disease: cold avoidance, analgesicsModerate to severe or recalcitrant disease: plasmapheresis, steroids, cytotoxic agents (cyclophosphamide); rituximab

Symptomatic management of vasculitis and/or hyperviscosity and limit damage caused by circulating immune complexes
Limit or suppress B-lymphocyte proliferation.
Eradicate HCV (if applicable, CGs types II and III) (2)[C].

Most important to treat underlying disease
Asymptomatic: Observe.
Mild disease: cold avoidance, analgesics
Moderate to severe or recalcitrant disease: plasmapheresis, steroids, cytotoxic agents (cyclophosphamide); rituximab

MEDICATION

Type ITreatment of underlying lymphoproliferative disease as appropriate (chemotherapy, radiation therapy) (7,8)[B]Non malignancy-associated: oral prednisone or cyclophosphamide
Types II and IIIAntiviral HCV therapy as appropriate: Pegylated interferon-в•¬в–’ and ribavirin have shown satisfactory response; hepatitis B treatment as appropriate (consider tenofovir, entecavir)Treatments are reserved for severe, recalcitrant CG (e.g., glomerulonephritis, skin ulcers, peripheral neuropathy) in infectious and non-infection-related populations:Rituximab (chimeric monoclonal antibody directed against CD20) has shown potential in relapse and long term control (9)[C].

Treatment of underlying lymphoproliferative disease as appropriate (chemotherapy, radiation therapy) (7,8)[B]
Non malignancy-associated: oral prednisone or cyclophosphamide

Antiviral HCV therapy as appropriate: Pegylated interferon-в•¬в–’ and ribavirin have shown satisfactory response; hepatitis B treatment as appropriate (consider tenofovir, entecavir)
Treatments are reserved for severe, recalcitrant CG (e.g., glomerulonephritis, skin ulcers, peripheral neuropathy) in infectious and non-infection-related populations:
Rituximab (chimeric monoclonal antibody directed against CD20) has shown potential in relapse and long term control (9)[C].

ONGOING CARE

DIET

PATIENT EDUCATION

PROGNOSIS

In mixed CG, overall prognosis worse with severe disease (glomerulonephritis, neuropathy, vasculitis), underlying lymphoproliferative disease.Mean survival: 50-60% at 10 years after diagnosis
In patients with noninfectious mixed CG vasculitis, the main prognostic factors are age >65 years, pulmonary and GI involvement, and renal failure (6)[B].
In patients with HCV-associated mixed CG vasculitis, the main cause of mortality remains renal disease, whereas immunosuppression significantly increases death due to infectious causes. Response to antiviral treatment incurs decreased mortality due to cryoglobulinemia vasculitis.

Mean survival: 50-60% at 10 years after diagnosis

REFERENCES

ADDITIONAL READING

Alpers ГЎCE, Smith ГЎKD. Cryoglobulinemia and renal disease. Curr Opin Nephrol Hypertens. 2008;17(3):243-249.
Anis ГЎS, Abbas ГЎK, Mubarak ГЎM, et al. Vasculitis with renal involvement in essential mixed cryoglobulinemia: case report and mini-review. World J Clin Cases. 2014;2(5):160-166.
Damoiseaux ГЎJ. The diagnosis and classification of the cryoglobulinemic syndrome. Autoimmun Rev. 2014;13(4-5):359-362.
De Vita ГЎS. Treatment of mixed cryoglobulinemia: a rheumatology perspective. Clin Exp Rheumatol. 2011;29(1 Suppl 64):S99-S103.
Della Rossa ГЎA, Cioffi ГЎE, Elefante ГЎE, et al. Systemic vasculitis: an annual critical digest of the most recent literature. Clin Exp Rheumatol. 2014;32(3 Suppl 82):S98-S105.
Fabrizi ГЎF, Dixit ГЎV, Messa ГЎP. Antiviral therapy of symptomatic HCV-associated mixed cryoglobulinemia: meta-analysis of clinical studies. J Med Virol. 2013;85(6):1019-1027.
Ferri ГЎC, Antonelli ГЎA, Mascia ГЎMT, et al. B-cells and mixed cryoglobulinemia. Autoimmun Rev. 2007;7(2):114-120.
Ferri ГЎC, Cacoub ГЎP, Mazzaro ГЎC, et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev. 2011;11(1):48-55.
Humphries ГЎK, Darling ГЎJM, Barritt ГЎASIV. Membranoproliferative glomerulonephritis, type II cryoglobulinemia and triple therapy for hepatitis C: a case series and review of the literature. Dig Dis Sci. 2014;59(8):2007-2012.
Landau ГЎD, Scerra ГЎS, Sene ГЎD, et al. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy. J Rheumatol. 2010;37(3):615-621.
Monti ГЎG, Saccardo ГЎF, Castelnovo ГЎL, et al. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study. Autoimmun Rev. 2014;13(6):609-614.
Motyckova ГЎG, Murali ГЎM. Laboratory testing for cryoglobulins. Am J Hematol. 2011;86(6):500-502.
Pietrogrande ГЎM, De Vita ГЎS, Zignego ГЎAL, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev. 2011;10(8):444-454.
Ramos-Casals ГЎM, Stone ГЎJH, Cid ГЎMC, et al. The cryoglobulinaemias. Lancet. 2012;379(9813):348-360.
Saadoun ГЎD, Resche Rigon ГЎM, Thibault ГЎV, et al. Peg-IFNв•¬в–’/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis. 2014;73(5):831-837.
Sneller ГЎMC, Hu ГЎZ, Langford ГЎCA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum. 2012;64(3):835-842.
Takada ГЎS, Shimizu ГЎT, Hadano ГЎY, et al. Cryoglobulinemia (review). Mol Med Rep. 2012;6(1):3-8.
Terrier ГЎB, Krastinova ГЎE, Marie ГЎI, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119(25):5996-6004.

CODES

ICD10

ICD9

SNOMED

cryoglobulinemia (disorder)
Monoclonal cryoimmunoglobulinemia (disorder)
Mixed polyclonal cryoimmunoglobulinemia (disorder)

CLINICAL PEARLS

CGs are circulating Igs that precipitate at cold temperatures (below 37 в–‘C) and dissolve on rewarming.
Type I: associated with lymphoproliferative disorders (e.g., multiple myeloma, Waldenstr Г‚m macroglobulinemia, monoclonal gammopathy of undetermined significance, and chronic lymphocytic leukemia)
Type II (mixed cryoglobulinemia): main association with hepatitis C (40-90% are hepatitis C-positive)
Type III (mixed cryoglobulinemia): high association with chronic infection and inflammatory states
Initial laboratory evaluation: CBC with peripheral smear, electrolytes, LFTs, BUN, creatinine, urinalysis, rheumatoid factor
Specific workup for underlying etiology:Serologic test for CGsSerum complement levels (low C4, normal or slightly decreased C3)Serologic tests for hepatitis B and C, HIVRheumatologic (antinuclear antibodies, ANCA)

Serologic test for CGs
Serum complement levels (low C4, normal or slightly decreased C3)
Serologic tests for hepatitis B and C, HIV
Rheumatologic (antinuclear antibodies, ANCA)