title: Mixed cryoglobulinemia.
abstract: Mixed cryoglobulinemia (MC), type II and type III, refers to the presence of circulating cryoprecipitable immune complexes in the serum and manifests clinically by a classical triad of purpura, weakness and arthralgias. It is considered to be a rare disorder, but its true prevalence remains unknown. The disease is more common in Southern Europe than in Northern Europe or Northern America. The prevalence of 'essential' MC is reported as approximately 1:100,000 (with a female-to-male ratio 3:1), but this term is now used to refer to a minority of MC patients only. MC is characterized by variable organ involvement including skin lesions (orthostatic purpura, ulcers), chronic hepatitis, membranoproliferative glomerulonephritis, peripheral neuropathy, diffuse vasculitis, and, less frequently, interstitial lung involvement and endocrine disorders. Some patients may develop lymphatic and hepatic malignancies, usually as a late complication. MC may be associated with numerous infectious or immunological diseases. When isolated, MC may represent a distinct disease, the so-called 'essential' MC. The etiopathogenesis of MC is not completely understood. Hepatitis C virus (HCV) infection is suggested to play a causative role, with the contribution of genetic and/or environmental factors. Moreover, MC may be associated with other infectious agents or immunological disorders, such as human immunodeficiency virus (HIV) infection or primary Sjögren's syndrome. Diagnosis is based on clinical and laboratory findings. Circulating mixed cryoglobulins, low C4 levels and orthostatic skin purpura are the hallmarks of the disease. Leukocytoclastic vasculitis involving medium- and, more often, small-sized blood vessels is the typical pathological finding, easily detectable by means of skin biopsy of recent vasculitic lesions. Differential diagnoses include a wide range of systemic, infectious and neoplastic disorders, mainly autoimmune hepatitis, Sjögren's syndrome, polyarthritis, and B-cell lymphomas. The first-line treatment of MC should focus on eradication of HCV by combined interferon-ribavirin treatment. Pathogenetic treatments (immunosuppressors, corticosteroids, and/or plasmapheresis) should be tailored to each patient according to the progression and severity of the clinical manifestations. Long-term monitoring is recommended in all MC patients to assure timely diagnosis and treatment of the life-threatening complications. The overall prognosis is poorer in patients with renal disease, liver failure, lymphoproliferative disease and malignancies.
authors.affiliation: Dipartimento Medicine e Specialità Mediche, Cattedra ed U,O,C, di Reumatologia, Università di Modena & Reggio Emilia, Modena, Italy. clferri@unimo.it
authors.forename: Clodoveo
authors.initials: C
authors.lastname: Ferri
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D003449:Cryoglobulinemia / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology / Q000503:physiopathology; D005260:Female; D006526:Hepatitis C / Q000150:complications / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D000998:Antiviral Agents; D007166:Immunosuppressive Agents
references.citation: N Engl J Med. 1994 Mar 17;330(11):751-6
references.pmid: 8107741
references.citation: Arthritis Res Ther. 2004;6(2):R137-41
references.pmid: 15059277
references.citation: Clin Immunol Immunopathol. 1998 May;87(2):124-9
references.pmid: 9614926
references.citation: Blood. 1993 Mar 1;81(5):1132-6
references.pmid: 8382969
references.citation: Nephrol Dial Transplant. 1999 Jun;14(6):1558-60
references.pmid: 10383026
references.citation: QJM. 1995 Feb;88(2):115-26
references.pmid: 7704562
references.citation: Ann Rheum Dis. 2000 Jan;59(1):20-5
references.pmid: 10627422
references.citation: J Hepatol. 2005 May;42(5):632-8
references.pmid: 15826710
references.citation: Clin Exp Rheumatol. 1991 Nov-Dec;9(6):621-4
references.pmid: 1662567
references.citation: Curr Opin Rheumatol. 2000 Jul;12(4):295-9
references.pmid: 10910182
references.citation: J Infect. 2006 Apr;52(4):294-9
references.pmid: 16026843
references.citation: Acta Haematol. 1988;79(1):20-5
references.pmid: 3124457
references.citation: J Clin Pathol. 2002 Jan;55(1):4-13
references.pmid: 11825916
references.citation: Arthritis Rheum. 2006 Nov;54(11):3696-706
references.pmid: 17075881
references.citation: Ann N Y Acad Sci. 2007 Jun;1107:308-18
references.pmid: 17804559
references.citation: Gastroenterol Clin Biol. 1999 Mar;23(3):403-6
references.pmid: 10384347
references.citation: Blood. 1996 Dec 15;88(12):4638-45
references.pmid: 8977256
references.citation: Clin Exp Rheumatol. 2008 Jan-Feb;26(1 Suppl 48):S39-47
references.pmid: 18570753
references.citation: JAMA. 1999 May 5;281(17):1588
references.pmid: 10235149
references.citation: Acta Haematol. 1983;70(2):73-82
references.pmid: 6408882
references.citation: Ann Intern Med. 2000 Oct 17;133(8):592-9
references.pmid: 11033586
references.citation: Semin Liver Dis. 2000;20(2):143-57
references.pmid: 10946420
references.citation: Blood. 1993 Dec 15;82(12):3701-4
references.pmid: 8260706
references.citation: Ann Intern Med. 2002 Oct 1;137(7):571-80
references.pmid: 12353944
references.citation: Arthritis Rheum. 1993 Oct;36(10):1341-9
references.pmid: 8216392
references.citation: Arthritis Rheum. 1996 May;39(5):767-72
references.pmid: 8639173
references.citation: Ann Rheum Dis. 2003 Dec;62(12):1230-3
references.pmid: 14644867
references.citation: J Rheumatol. 2005 Mar;32(3):484-8
references.pmid: 15742440
references.citation: J Hepatol. 1998 Dec;29(6):879-86
references.pmid: 9875633
references.citation: QJM. 2004 Aug;97(8):499-506
references.pmid: 15256607
references.citation: Arthritis Rheum. 2002 Mar;46(3):585-97
references.pmid: 11920393
references.citation: Blood. 1994 Nov 1;84(9):3047-53
references.pmid: 7949176
references.citation: Br J Rheumatol. 1994 Aug;33(8):791-2
references.pmid: 8055216
references.citation: N Engl J Med. 1977 Jun 30;296(26):1501-4
references.pmid: 865530
references.citation: JAMA. 2002 Aug 14;288(6):698-9
references.pmid: 12169072
references.citation: Ric Clin Lab. 1986 Apr-Jun;16(2):281-8
references.pmid: 2947311
references.citation: Medicine (Baltimore). 2001 Jan;80(1):1-8
references.pmid: 11204499
references.citation: Arthritis Rheum. 1995 Dec;38(12):1859-60
references.pmid: 8849361
references.citation: Hepatology. 1994 Apr;19(4):841-8
references.pmid: 8138255
references.citation: Ann Intern Med. 1995 Oct 15;123(8):615-20
references.pmid: 7677303
references.citation: Clin Exp Rheumatol. 1990 May-Jun;8(3):271-81
references.pmid: 2379342
references.citation: N Engl J Med. 1998 Nov 19;339(21):1485-92
references.pmid: 9819446
references.citation: Br J Rheumatol. 1996 Oct;35(10):978-82
references.pmid: 8883436
references.citation: Gastroenterology. 1994 May;106(5):1291-300
references.pmid: 7513667
references.citation: J Virol. 2008 Apr;82(7):3466-79
references.pmid: 18216094
references.citation: Blood. 2003 May 15;101(10):3818-26
references.pmid: 12506023
references.citation: Autoimmun Rev. 2006 Aug;5(7):493-8
references.pmid: 16920576
references.citation: Hepatology. 2005 Nov;42(5):1019-27
references.pmid: 16231354
references.citation: Curr Opin Rheumatol. 2007 Nov;19(6):619-25
references.pmid: 17917544
references.citation: Arthritis Rheum. 1999 Dec;42(12):2507-16
references.pmid: 10615995
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4262-7
references.pmid: 14999097
references.citation: Rheumatology (Oxford). 2005 Jan;44(1):89-94
references.pmid: 15381790
references.citation: Am J Med. 1979 May;66(5):748-56
references.pmid: 443251
references.citation: J Infect Dis. 1990 Aug;162(2):569-70
references.pmid: 2115556
references.citation: J Intern Med. 1994 Jul;236(1):31-6
references.pmid: 8021570
references.citation: Blood. 1995 Sep 1;86(5):1887-92
references.pmid: 7655017
references.citation: Dig Liver Dis. 2007 Sep;39 Suppl 1:S61-4
references.pmid: 17936226
references.citation: Am J Med. 1966 Jun;40(6):837-56
references.pmid: 4956871
references.citation: Ter Arkh. 2004;76(8):61-8
references.pmid: 15471400
references.citation: Am J Med. 1974 Nov;57(5):775-88
references.pmid: 4216269
references.citation: Ann Rheum Dis. 2000 Jun;59(6):490-2
references.pmid: 10885976
references.citation: Cancer. 1996 Jun 15;77(12):2604-13
references.pmid: 8640712
references.citation: Muscle Nerve. 2005 Mar;31(3):382-5
references.pmid: 15515001
references.citation: Arthritis Rheum. 1997 Nov;40(11):2007-15
references.pmid: 9365090
references.citation: Br J Haematol. 1994 Oct;88(2):392-4
references.pmid: 7803287
references.citation: Semin Arthritis Rheum. 2004 Jun;33(6):355-74
references.pmid: 15190522
references.citation: Clin Exp Rheumatol. 1997 Nov-Dec;15(6):655-8
references.pmid: 9444422
references.citation: J Immunol Methods. 1994 Jul 12;173(1):63-75
references.pmid: 8034987
references.citation: J Rheumatol. 2000 Sep;27(9):2172-8
references.pmid: 10990230
references.citation: Ann Intern Med. 1999 Feb 2;130(3):226-30
references.pmid: 10049201
references.citation: Nephron. 1986;43(4):246-53
references.pmid: 3736735
references.citation: Lancet. 1991 Aug 3;338(8762):277-80
references.pmid: 1677111
references.citation: Hepatology. 2006 May;43(5):1166-7; author reply 1167-8
references.pmid: 16628675
references.citation: Ann Intern Med. 2002 May 21;136(10):747-57
references.pmid: 12020143
references.citation: Autoimmun Rev. 2005 Jan;4(1):8-15
references.pmid: 15652773
references.citation: Nephrol Dial Transplant. 1993;8(11):1193-8
references.pmid: 8302454
references.citation: Dig Liver Dis. 2007 Sep;39 Suppl 1:S13-21
references.pmid: 17936215
references.citation: Arch Pathol Lab Med. 1999 Feb;123(2):119-25
references.pmid: 10050784
references.citation: J Rheumatol. 1996 Sep;23(9):1641-3
references.pmid: 8877939
references.citation: Ann Rheum Dis. 2008 Oct;67(10):1431-6
references.pmid: 18178690
references.citation: Arch Intern Med. 2005 Jan 10;165(1):101-5
references.pmid: 15642884
references.citation: Ann Rheum Dis. 2002 Jun;61(6):554-8
references.pmid: 12006334
references.citation: Blood. 1991 Dec 15;78(12):3142-7
references.pmid: 1742481
references.citation: Clin Exp Immunol. 1973 Dec;15(4):483-96
references.pmid: 4778718
references.citation: J Hepatol. 2005 Mar;42(3):315-22
references.pmid: 15791697
references.citation: Am J Med. 1962 Jan;32:142-7
references.pmid: 14466769
references.citation: Autoimmun Rev. 2007 Dec;7(2):114-20
references.pmid: 18035320
references.citation: Cancer Sci. 2004 Sep;95(9):745-52
references.pmid: 15471561
references.citation: J Hepatol. 1992 Jul;15(3):382-6
references.pmid: 1332999
references.citation: Blood. 2003 May 15;101(10):3827-34
references.pmid: 12560225
references.citation: Ann Intern Med. 1992 Oct 1;117(7):573-7
references.pmid: 1326246
references.citation: Arthritis Rheum. 2008 Feb;58(2):604-11
references.pmid: 18240235
references.citation: Dig Liver Dis. 2007 Jan;39(1):2-17
references.pmid: 16884964
references.citation: Medicine (Baltimore). 2005 Mar;84(2):81-89
references.pmid: 15758837
references.citation: J Rheumatol. 2005 Jan;32(1):143-9
references.pmid: 15630740
references.citation: J Hepatol. 2005 Mar;42(3):334-40
references.pmid: 15710215
references.citation: Clin Nephrol. 2004 Feb;61(2):144-50
references.pmid: 14989635
references.citation: Am J Med. 1980 Aug;69(2):287-308
references.pmid: 6996482
references.citation: Science. 1998 Oct 30;282(5390):938-41
references.pmid: 9794763
references.citation: Ann Rheum Dis. 2008 Mar;67(3):283-7
references.pmid: 17644544
references.citation: Rheumatology (Oxford). 2007 Nov;46(11):1657-61
references.pmid: 17893101
references.citation: Arthritis Rheum. 2002 Mar;46(3):741-7
references.pmid: 11920410
references.citation: Rheumatology (Oxford). 2004 Feb;43(2):238-40
references.pmid: 13130149
references.citation: Science. 1989 Apr 21;244(4902):359-62
references.pmid: 2523562
references.citation: Am J Med. 1989 Nov;87(5):519-24
references.pmid: 2816967
references.citation: Nephrol Dial Transplant. 2004 Dec;19(12):3054-61
references.pmid: 15494358
references.citation: Reumatismo. 2002 Oct-Dec;54(4):316-23
references.pmid: 12563365
references.citation: Clin Rev Allergy Immunol. 1997 Spring;15(1):97-119
references.pmid: 9209804
references.citation: Springer Semin Immunopathol. 1997;19(1):99-110
references.pmid: 9266634
references.citation: Clin Exp Rheumatol. 1996 Mar-Apr;14(2):219-20
references.pmid: 8737733
references.citation: Arthritis Rheum. 2004 Jul;50(7):2305-8
references.pmid: 15248231
references.citation: N Engl J Med. 1992 Nov 19;327(21):1490-5
references.pmid: 1383822
references.citation: Curr Opin Rheumatol. 2006 Jan;18(1):54-63
references.pmid: 16344620
references.citation: Clin Exp Rheumatol. 1998 Jul-Aug;16(4):506
references.pmid: 9706438
references.citation: Eur J Cancer. 1991;27 Suppl 4:S81-2
references.pmid: 1799489
references.citation: Br J Rheumatol. 1997 Mar;36(3):360-5
references.pmid: 9133969
references.citation: J Rheumatol. 1992 Jun;19(6):889-95
references.pmid: 1328632
references.citation: Clin Exp Rheumatol. 2002 Sep-Oct;20(5):693-6
references.pmid: 12412202