eMedicine Specialties > Rheumatology > Vasculitis

Cryoglobulinemia: Treatment & Medication

Author: Craig Ainsworth, MD, Resident Physician, Department of Internal Medicine, Eisenhower Army Medical Center, Fort Gordon, GA
Coauthor(s): Colin C Edgerton, MD, Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Chief of Rheumatology Service, Eisenhower Army Medical Center; Robert John Oglesby, MD, Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Contributor Information and Disclosures

Updated: Jul 17, 2009

Treatment

Medical Care

The goal of therapy is to treat underlying conditions, as well as to limit the precipitant cryoglobulin and the resultant inflammatory effects. Thus, HCV testing is required. HCV-antibody or HCV-RNA testing may be diagnostic. If HCV test results are negative and clinical suspicion remains high, these tests may be performed on the cryoprecipitate. Asymptomatic cryoglobulinemia does not require treatment. Some authors recommend intervening as little as possible except when faced with severe deterioration of renal or neurologic function. Secondary cryoglobulinemia is best managed with treatment of the underlying malignancy or associated disease. Otherwise, cryoglobulinemia is treated simply with suppression of the immune response. A paucity of controlled studies evaluating the relative efficacy of various therapies limits the use of existing data.

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used in patients with arthralgia and fatigue.
  • Immunosuppressive medications (eg, corticosteroid therapy and/or cyclophosphamide or azathioprine) are indicated upon evidence of organ involvement such as vasculitis, renal disease, progressive neurologic findings, or disabling skin manifestations.
  • Plasmapheresis is indicated for severe or life-threatening complications related to in vivo cryoprecipitation or serum hyperviscosity. Concomitant use of high-dose corticosteroids and cytotoxic agents is recommended for reduction of immunoglobulin production. Some authors recommend using concomitant cytotoxic medications or corticosteroids to reduce a rebound phenomenon that may develop after plasmapheresis.
  • Pegylated interferon alfa (IFN-alfa) combined with ribavirin has demonstrated efficacy in patients with cryoglobulinemia associated with hepatitis C, and efficacy in patients with chronic myelogenous leukemias and low-grade lymphomas has been reported. The details of therapy and the recommended approach vary based on the clinical setting, and expert opinion should be sought.
  • Case reports have detailed the remission of hepatitis B–related cryoglobulinemic vasculitis with entecavir therapy.38
  • Small and uncontrolled studies suggest the anti-CD20 chimeric monoclonal antibody rituximab is effective in controlling disease manifestations such as vasculitis, peripheral neuropathy, arthralgias, low-grade B-cell lymphomas, renal disease, and fever.39,40 Rituximab therapy has been used predominately in HCV-related mixed cryoglobulinemia refractory to or unsuitable for corticosteroids and antiviral (IFN-alfa) therapy. Rituximab therapy is reportedly well tolerated in this patient population; however, treatment results in increased titers of HCV-RNA of undetermined significance. The National Institutes of Health has launched a large trial of rituximab in the treatment of mixed cryoglobulinemia.

Consultations

  • Rheumatologist or clinical immunologist
  • Nephrologist upon evidence of renal disease (ie, hypertension, abnormal findings on urinalysis)
  • Hematologist upon evidence of underlying hematological disease or for plasmapheresis
  • Gastroenterologist or hepatologist for patients with underlying hepatitis

Medication

The overall aim of therapy is treatment of any underlying condition and general suppression of the immune response. Mild anti-inflammatory medications (eg, NSAIDs) are effective in mild cases, and corticosteroid therapy is reserved for the more severe or refractory cases. Patients who require potent immunosuppression or other more aggressive therapies for severe disease should be treated by a specialist. Cyclophosphamide may be used as a steroid-sparing agent or administered concomitantly in severe cases of vasculitis, particularly in patients with renal disease. Azathioprine is commonly used as a steroid-sparing agent, and chlorambucil has also been used for severe vasculitis.

Nonsteroidal anti-inflammatory drugs

NSAIDs such as ibuprofen, naproxen, and indomethacin have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. NSAIDs may have additional mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions. NSAIDs are used to reduce the resultant inflammatory response of cryoglobulin precipitation.


Ibuprofen (Advil, Motrin, Excedrin IB, Ibuprin)

NSAIDs are the DOC in patients with mild symptoms of arthralgia or fatigue. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Adult

600-800 mg PO tid/qid

Pediatric

30-40 mg/kg/d PO divided tid/qid

Coadministration with aspirin increases the risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, ACE inhibitors, angiotensin II receptor blockers, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; coadministration with ACE inhibitors, angiotensin II receptor blockers, and potassium-sparing diuretics may result in hyperkalemia; may increase PT when combined with anticoagulants or aggravate bleeding tendency because of the antiplatelet effect of NSAIDs; phenytoin levels may be increased when administered concurrently

Documented hypersensitivity; peptic ulcer disease; history of GI bleeding or perforation; renal insufficiency; anticoagulation; coagulopathy

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Most common toxicities include gastrointestinal manifestations such as nausea, abdominal pain, peptic ulcer disease, and renal insufficiency; may cause increased blood pressure in patients with hypertension due to blunting of effects of antihypertensive medications; patients with congestive heart failure may have exacerbations due to fluid and sodium retention; caution in coagulation abnormalities or during anticoagulant therapy

Corticosteroids

These medications are used to reduce the resultant immune response from cryoglobulin precipitation, particularly in patients with more severe symptoms or some evidence of organ damage.


Prednisone (Sterapred)

DOC in patients with evidence of acute vasculitis.

Adult

1 mg/kg/d PO in divided doses; up to 120 mg/d has been reported

Pediatric

2-3 mg/kg/d PO

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in severe bacterial, viral, or fungal infection; active peptic ulcer disease; diabetes mellitus; toxicities include weight gain, dyspepsia, mood changes, infection, peptic ulcer disease, hypertension, diabetes mellitus, osteoporosis, avascular necrosis, cataracts, glaucoma, myopathy, and skin changes; growth retardation in children; abrupt discontinuation may result in adrenal crisis

Immunosuppressive agents

These are commonly used as steroid-sparing agents.


Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, interfering with growth of normal and neoplastic cells.

Adult

1-5 mg/kg/d PO

Pediatric

Administer as in adults

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Documented hypersensitivity; infection; severely depressed bone marrow function; severe cytopenias

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Toxicities include nausea and vomiting, leukopenia, thrombocytopenia, anemia, infection, alopecia, hemorrhagic cystitis, infertility, teratogenicity, and increased risk of infection; monitor CBC count and UA at regular intervals


Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Adult

2-3 mg/kg/d PO single or divided dose
1 mg/kg/d initial; increase depending on clinical and hematologic response and toxicity

Pediatric

Administer as in adults

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Documented hypersensitivity; low levels of serum thiopurine methyltransferase (TPMT); active infection (relative); severe cytopenias (relative)

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Nausea and vomiting; hematologic toxicities may occur; check TPMT level prior to initiation of therapy; pancreatitis rarely occurs; monitor CBC count and LFTs at regular intervals; may also monitor 6-thioguanine (6-TG) and 6-methyl mercaptopurine (6-MMP) levels


Chlorambucil (Leukeran)

Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Adult

0.1-0.2 mg/kg/d PO

Pediatric

Administer as in adults

Documented hypersensitivity; previous resistance to medication; active infection (relative)

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in history of seizure disorders or in patients diagnosed with bone marrow suppression; gastrointestinal effects, dermatitis or erythema multiforme, cystitis, pulmonary fibrosis, hepatotoxicity, infertility, teratogenic effects, peripheral neuropathy, and secondary malignancy may occur; monitor CBC count and LFTs at regular intervals

Interferons

These agents are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. IFN-alfa is generally administered subcutaneously.


Interferon alfa-2b (Intron A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Has antiviral activity in HCV infection.

Adult

Not recommended without consultation

Pediatric

Not established

Potential risk of renal failure when administered concurrently with interleukin-2; theophylline may increase IFN-alfa toxicity by reducing clearance; cimetidine may increase antitumor effects of IFN-alfa; zidovudine and vinblastine may increase toxicity of IFN-alfa

Documented hypersensitivity; patients who have anaphylactic sensitivity to mouse IgG, egg protein, or neomycin; autoimmune disease (relative)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Fatigue; headache; arthralgias; myalgias; fever; nausea; autoimmunity; depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage is reported in association with IFN-a therapy; prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cell, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed; whether continued treatment after that time is beneficial is not known


Peginterferon alfa-2a (Pegasys)

Used in combination with ribavirin to treat patient with chronic HCV infection who have compensated liver disease and have not received IFN-alfa previously. Consists of interferon alfa-2a attached to a 40-kD branched PEG molecule. Predominantly metabolized by the liver.

Adult

180 mcg SC qwk

Pediatric

Not established

Theophylline may increase toxicity by reducing clearance; cimetidine may increase the antitumor effects; zidovudine and vinblastine may increase toxicity

Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <70,000/µL

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis, aggressive behavior, hallucinations, violent behavior, suicidal ideation, suicide attempt, suicide, homicidal ideation [rare]), even without previous history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia; neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities


Peginterferon alfa-2b (PEG-Intron)

Escherichia coli recombinant product. Used to treat chronic HCV infection in patients not previously treated with INF-alfa who have compensated liver disease. Exerts cellular activities by binding to specific membrane receptors on cell surface, which, in turn, may suppress cell proliferation and may enhance phagocytic activity of macrophages. May also increase cytotoxicity of lymphocytes for target cells and inhibit virus replication in virus-infected cells.

Adult

Inject SC qwk for 1 y using weight-based dosing as follows:
37-45 kg: 40 mcg (0.4 mL of 100 mcg/mL)
46-56 kg: 50 mcg (0.5 mL of 100 mcg/mL)
57-72 kg: 64 mcg (0.4 mL of 160 mcg/mL)
73-88 kg: 80 mcg (0.5 mL of 160 mcg/mL)
89-106 kg: 96 mcg (0.4 mL of 240 mcg/mL)
107-136 kg: 120 mcg (0.5 mL of 240 mcg/mL)
137-160 kg: 150 mcg (0.5 mL of 300 mcg/mL)

Pediatric

Not established

Concurrent administration with interleukin 2 may increase nephrotoxicity; theophylline, zidovudine, and vinblastine may increase toxicity; cimetidine may increase antitumor effects

Documented hypersensitivity; autoimmune hepatitis; pancreatitis; colitis

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis, aggressive behavior, hallucinations, violent behavior, suicidal ideation, suicide attempt, suicide, homicidal ideation [rare]), even without previous history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia; neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities

Antiviral agents

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.


Ribavirin (Virazole)

Antiviral nucleoside analogs. Chemical name is 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide. Given alone, has little effect on the course of HCV infection. When used with IFN, significantly augments rate of sustained virologic response.

Adult

10.6 mg/kg/d PO or divided bid

Pediatric

Not established

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Closely monitor patients with COPD and asthma for deterioration of respiratory function

Antiviral Agent, Oral

This agent inhibits the viral reverse transcriptase enzyme, which limits viral replication.


Entecavir (Baraclude)

Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic hepatitis B infection. Available as tab and oral solution (0.05 mg/mL; 0.5 mg = 10 mL).

Adult

Treatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc

CrCl 30-49 mL/min: 0.25 mg PO qd or 0.5 mg q48h
CrCl 10-29 mL/min: 0.15 mg PO qd or 0.5 mg q72h
CrCl <10 mL/min: 0.05 mg PO qd or 0.5 mg qwk

Receiving lamivudine or lamivudine resistance: 1 mg PO qd 2 h ac or 2 h pc

CrCl 30-49 mL/min: 0.5 mg PO qd or 1 mg q48h
CrCl 10-29 mL/min: 0.3 mg PO qd or 1 mg q72h
CrCl <10 mL/min: 0.1 mg PO qd or 1 mg qwk

Pediatric

<16 years: Not established
>16 years: Administer as in adults

Not a substrate, inhibitor, or inducer of cytochrome P450; coadministration with drugs that reduce renal function (eg, aminoglycosides, cidofovir, cyclosporine) or that compete for active tubular secretion (eg, probenecid, salicylates) may increase serum concentration of either entecavir or coadministered drug

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Reduce dose with renal impairment; if on hemodialysis, administer afterwards; common adverse effects include headache, tiredness, dizziness, and nausea; may elevate liver enzyme levels; may cause lactic acidosis; severe acute exacerbations of hepatitis B may occur in patients who discontinue antihepatitis B therapy

Antineoplastic agents

These agents inhibit cell growth and proliferation.


Rituximab (Rituxan)

Genetically engineered human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.
Immunomodulates response against malignant cells.

Adult

60-75 mg/m2 IV as a single dose; repeat q21d
Alternatively, 20-30 mg/m2/d for 2-3 d; repeat in 4 wk

Pediatric

Not established

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypotension, bronchospasm, and angioedema may occur; discontinue treatment if life-threatening cardiac arrhythmias occur

More on Cryoglobulinemia

Overview: Cryoglobulinemia
Differential Diagnoses & Workup: Cryoglobulinemia
Treatment & Medication: Cryoglobulinemia
Follow-up: Cryoglobulinemia
Multimedia: Cryoglobulinemia
References
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Further Reading

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Keywords

cryoglobulinemia, cryoproteinemia, cryoglobulins, immunoglobulins, essential cryoglobulinemia, simple cryoglobulinemia, type I cryoglobulinemia, type II cryoglobulinemia, type III cryoglobulinemia, mixed cryoglobulinemia, essential cryoglobulinemia, idiopathic cryoglobulinemia, hepatitis C virus, HCV, secondary cryoglobulinemia, glomerulonephritis, chronic vasculitis, cryoprecipitation, systemic lupus erythematosus, SLE, Sjögren syndrome, Sjögren's syndrome, hyperviscosity, thrombosis, acrocyanosis, retinal hemorrhage, Raynaud phenomenon, Raynaud's phenomenon, livedo reticularis, purpura, arterial thrombosis, multiple myeloma, Waldenström macroglobulinemia, Waldenström's macroglobulinemia, chronic liver disease

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Contributor Information and Disclosures

Author

Craig Ainsworth, MD, Resident Physician, Department of Internal Medicine, Eisenhower Army Medical Center, Fort Gordon, GA
Craig Ainsworth, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Colin C Edgerton, MD, Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Chief of Rheumatology Service, Eisenhower Army Medical Center
Colin C Edgerton, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Robert John Oglesby, MD, Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Robert John Oglesby, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and Arthritis Foundation
Disclosure: Nothing to disclose.

Medical Editor

Kristine M Lohr, MD, MS, Program Director, Professor, Department of Internal Medicine, Division of Rheumatology and Women's Health, University of Kentucky School of Medicine
Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Medical Women's Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Lawrence H Brent, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, and American College of Rheumatology
Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

 
 
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