Cryoglobulinaemia = فرط غلوبولينات البرد في الدم |
Cryoglobulinaemia
Cryoglobulins are single or mixed immunoglobulins that undergo reversible precipitation at low temperatures. Several types of cryoglobulins have been identified, and the potential clinical manifestations vary by cryoglobulin type. Cryoglobulinemia is characterized by the presence of cryoglobulins in the serum. This may result in a clinical syndrome of systemic inflammation (most commonly affecting the kidneys and skin) caused by cryoglobulin-containing immune complexes. Cryoglobulinemia may be classified based on cryoglobulin composition with the Brouet classification, which is as follows:
Cryoglobulinemia may also be classified based on the association of the syndrome with an underlying disease. Cryoglobulinemia without an associated disease has been known as essential, or idiopathic, cryoglobulinemia. However, the discovery of a close association between hepatitis C virus (HCV) and mixed cryoglobulinemia has cast doubt on the existence of essential, or idiopathic, cryoglobulinemia.1 Cryoglobulinemia associated with a particular disease (lymphoproliferative disorder, autoimmune disease, infectious disease) is known as secondary cryoglobulinemia. PathophysiologyThe mechanisms of cryoprecipitation are poorly understood, but several factors have been investigated. The solubility of cryoglobulins has been found to be partially related to the structure of component immunoglobulin heavy and light chains.2,3,4 Alteration in protein conformation with temperature changes also leads to decreased solubility and subsequent vasculitic damage.5,6 The ratio of antibody to antigen in circulating cryoglobulin aggregates or immune complexes affects the rate of clearance from the circulation and the resultant rate and location of tissue deposition.7 Some of the sequelae of cryoglobulinemia are thought to be related to immune-complex disease (eg, glomerulonephritis, chronic vasculitis), but not all persons with cryoglobulinemia present with these manifestations. Individuals with cryoglobulinemia may have intravascular cryoglobulin deposits, a reduced level of complement, and complement fragments (C3a, C5a) that act as chemotactic mediators of inflammation; however, the pathophysiologic process of this disease has not been fully explained. Other sequelae are directly related to cryoprecipitation in vivo, including plugging and thrombosis of small arteries and capillaries in the extremities (gangrene) and glomeruli (acute renal failure). Circulating large–molecular-weight cryoprotein complexes, even when unprecipitated in vivo, can lead to clinical hyperviscosity syndrome. Type I cryoglobulins are usually monoclonal IgM and, less frequently, IgG, IgA, or light chains. Type I cryoglobulins rarely have RF activity and do not activate complement in vitro. This disorder is typically related to an underlying lymphoproliferative disease and, as such, may be clinically indistinguishable from Waldenström macroglobulinemia, multiple myeloma, or chronic lymphocytic leukemia. Type I cryoglobulinemia may result in hyperviscosity due to high levels of circulating monoclonal cryoglobulin, leading to physical obstruction of vessels. Concentrations may reach up to 8 g/L. In addition, nonobstructive damage may be mediated by immune complex deposition and subsequent inflammatory vasculitis. Types II and III, also known as the mixed cryoglobulinemias, are associated with chronic inflammatory states such as systemic lupus erythematosus (SLE), Sjögren syndrome, and viral infections (particularly HCV). In these disorders, the IgG fraction is always polyclonal with either monoclonal (type II) or polyclonal (type III) IgM (rarely IgA or IgG) with RF activity (ability to bind IgG). B-cell clonal expansion, particularly RF-secreting cells, is a distinctive feature in many of these disease states.1,8,9,10 The resultant aggregates and immune complexes are thought to outstrip reticuloendothelial-clearing activity. Tissue damage results from immune complex deposition and complement activation. Of note, in HCV-related disease, HCV-related proteins are thought to play a direct role in pathogenesis and are present in damaged skin, blood vessels, and kidneys
Physical
Causes
Laboratory Studies
Imaging Studies
Procedures
Histologic FindingsSkin: Purpura are histologically characterized by dermal vasculitis that extends variably to the subcutaneous interstitial space. HCV-associated proteins have been found in vasculitic skin biopsy samples, suggesting a role for these antigens in pathogenesis of the lesions. Other organs: Autopsy studies have revealed unsuspected vasculitis of multiple organs (heart, lung, gastrointestinal tract, central nervous system, liver, muscle, adrenals).14 Histologic evaluation of affected lung, kidney, and muscle reveals eosinophilic material in the lumen of small vessels with frequent extension into the vessel intima and inflammation of the vessel wall.37 Although biopsy samples generally exhibit inflammatory vascular changes (eg, leukocytoclastic vasculitis in patients with vasculitic purpura), intraluminal cryoglobulin deposits may be observed, especially in renal glomeruli
Medical CareThe 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.
Consultations
MedicationThe 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 drugsNSAIDs 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.
Adult600-800 mg PO tid/qid Pediatric30-40 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
PregnancyB - 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 PrecautionsMost 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 CorticosteroidsThese 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.
Adult1 mg/kg/d PO in divided doses; up to 120 mg/d has been reported Pediatric2-3 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
Documented hypersensitivity
PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsCaution 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 agentsThese 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.
Adult1-5 mg/kg/d PO PediatricAdminister 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
PregnancyD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus PrecautionsToxicities 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.
Adult2-3 mg/kg/d PO single or divided dose PediatricAdminister 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)
PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsNausea 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.
Adult0.1-0.2 mg/kg/d PO PediatricAdminister as in adults
None reported
Documented hypersensitivity; previous resistance to medication; active infection (relative)
PregnancyD - Fetal risk shown in humans; use only if benefits outweigh risk to fetus PrecautionsCaution 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 InterferonsThese 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.
AdultNot recommended without consultation PediatricNot 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)
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsFatigue; 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.
Adult180 mcg SC qwk PediatricNot 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
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsInsomnia; 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.
AdultInject SC qwk for 1 y using weight-based dosing as follows: PediatricNot 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
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsInsomnia; 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 agentsNucleoside 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.
Adult10.6 mg/kg/d PO or divided bid PediatricNot established
Decreases zidovudine effects
Documented hypersensitivity
PregnancyX - Contraindicated; benefit does not outweigh risk PrecautionsClosely monitor patients with COPD and asthma for deterioration of respiratory function Antiviral Agent, OralThis 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).
AdultTreatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc Pediatric<16 years: Not established
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
Documented hypersensitivity
PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsReduce 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 agentsThese 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.
Adult60-75 mg/m2 IV as a single dose; repeat q21d PediatricNot established |