{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:48:53Z","timestamp":1791582533034,"version":"4.3.4"},"reference-count":118,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Intern Med"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cryoglobulinemia (CG) is defined by the presence of serum immunoglobulins that precipitate below 37\u00b0C and redissolve upon rewarming. It is classified into three types based on immunoglobulin composition. Type I, a rare form, involves monoclonal IgM or IgG and is linked to lymphoproliferative disorders. Types II and III are known as mixed CG (MC): Type II consists of polyclonal IgG and monoclonal IgM with rheumatoid factor (RF) activity, whereas Type III includes polyclonal IgG and polyclonal IgM with RF activity. MC is predominantly associated with hepatitis C virus (HCV) infection and involves B\u2010cell lymphoproliferation and autoantibody production. CG may lead to systemic vasculopathy, ranging from mild symptoms (purpura, asthenia, and arthralgia) to severe complications such as skin ulcers, peripheral neuropathy, renal involvement, and non\u2010Hodgkin lymphoma. Compared to MC, Type I is more often marked by severe cutaneous involvement (ulcers, gangrene), hyperviscosity, and a higher risk of morbidity due to the underlying hematologic malignancy. Management of Type I requires control of vasculopathy and treatment of the hematologic neoplasm, whereas MC demands antiviral therapy in all HCV\u2010associated or hepatitis B virus\u2013associated cases. Severe vasculopathy in both types may benefit from corticosteroids, immunomodulators, anti\u2010CD20 monoclonal antibodies, and plasma exchange. A multidisciplinary approach is essential for addressing both etiology and complications, thereby improving outcomes. This review summarizes the pathophysiology, clinical features, recent etiopathogenetic insights, and therapeutic advances related to the various forms of CG.<\/jats:p>","DOI":"10.1111\/joim.70042","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T03:58:25Z","timestamp":1764215905000},"page":"196-215","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Cryoglobulinemia: An update on classification, pathophysiology, clinical presentation, and management"],"prefix":"10.1111","volume":"299","author":[{"given":"Anna Linda","family":"Zignego","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine University of Florence  Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6800-9149","authenticated-orcid":false,"given":"Laura","family":"Gragnani","sequence":"additional","affiliation":[{"name":"Department of Translational Research and New Surgical and Medical Technologies University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Visentini","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine Sapienza University of Rome Laboratory affiliated to Istituto Pasteur Italia\u2010Fondazione Cenci Bolognetti  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Bomben","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco\u2010Hematology Unit Centro di Riferimento Oncologico di Aviano (CRO) IRCCS  Aviano Pordenone Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Arcaini","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of Pavia  Pavia Italy"},{"name":"Division of Hematology Fondazione IRCCS Policlinico San Matteo  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clodoveo","family":"Ferri","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences for Children and Adults University Hospital of Modena and Reggio Emilia  Modena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valter","family":"Gattei","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco\u2010Hematology Unit Centro di Riferimento Oncologico di Aviano (CRO) IRCCS  Aviano Pordenone Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Mazzaro","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Onco\u2010Hematology Unit Centro di Riferimento Oncologico di Aviano (CRO) IRCCS  Aviano Pordenone Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(74)90852-3"},{"issue":"4","key":"e_1_2_8_3_1","first-page":"316","article-title":"[Hepatitis C virus infection and arthritis. A clinico\u2010serological investigation of arthritis in patients with or without cryoglobulinemic syndrome]","volume":"54","author":"Fadda P","year":"2002","journal-title":"Reumatismo."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0009-4"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2020.05.004"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2016.09.006"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19112"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.280953"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.20220"},{"issue":"6","key":"e_1_2_8_10_1","first-page":"621","article-title":"Association between hepatitis C virus and mixed cryoglobulinemia [see comment]","volume":"9","author":"Ferri C","year":"1991","journal-title":"Clin Exp Rheumatol."},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13061032"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbspin.2019.01.016"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2011.150755"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37715"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2400092"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V69.2.677.677"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13868"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-719773"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.165.1.101"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.09.023"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-018-0077-4"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-020-04123-1"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.3109\/01913123.2014.952803"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26944"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0b013e318288925c"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13196"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0b013e3182a5cf71"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780341221"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s007050050100"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(91)92715-E"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2017.03.004"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(99)80239-6"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2006.06.008"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2106143"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1191\/096120398678920091"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1590-8658(07)80005-3"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2003.10.001"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.1999.tb00306.x"},{"issue":"9","key":"e_1_2_8_39_1","first-page":"1641","article-title":"Exacerbation of peripheral neuropathy during alpha\u2010interferon therapy in a patient with mixed cryoglobulinemia and hepatitis B virus infection","volume":"23","author":"La Civita L","year":"1996","journal-title":"J Rheumatol."},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1159\/000168641"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2011.01.008"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780390714"},{"issue":"57","key":"e_1_2_8_43_1","first-page":"84","article-title":"Efficacy of rituximab in severe and mild abdominal vasculitis in the course of mixed cryoglobulinemia","volume":"28","author":"Quartuccio L","year":"2010","journal-title":"Clin Exp Rheumatol."},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2010.218123"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/36.3.360"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2020.102589"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1994.tb05036.x"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1994.03520050033023"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2016.03.012"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i9.1697"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keh011"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-87-3-287"},{"key":"e_1_2_8_53_1","first-page":"S129","article-title":"The natural history of cryoglobulinemia: symptoms at onset and during follow\u2010up. A report by the Italian group for the study of cryoglobulinemias (GISC)","author":"Monti G","year":"1995","journal-title":"Clin Exp Rheumatol."},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2015.08.008"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/diseases6020035"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.580271"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/nep.12795"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000001575"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2012.10.014"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2016.03.018"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/0168-8278(92)90073-X"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31804"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v7.i3.327"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-07-170613"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2012.04653.x"},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.3008"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0303971101"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1590-8658(07)80009-0"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.12.011"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-353821"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-07-101717"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.06.029"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201142313"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1094871"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-221248"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i47.8910"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx635"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/41.3.290"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2012.671481"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.23608"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24745"},{"key":"e_1_2_8_82_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-020-03993-9"},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP3246"},{"key":"e_1_2_8_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.02.010"},{"key":"e_1_2_8_85_1","first-page":"1042","volume-title":"EULAR compendium on rheumatic diseases: London, BMJ","author":"Ferri C","year":"2012"},{"key":"e_1_2_8_86_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-023-01444-4"},{"key":"e_1_2_8_87_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/key157"},{"key":"e_1_2_8_88_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.04.024"},{"key":"e_1_2_8_89_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.14845"},{"key":"e_1_2_8_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28753"},{"key":"e_1_2_8_91_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389450117666160208145432"},{"key":"e_1_2_8_92_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32281"},{"key":"e_1_2_8_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.04.007"},{"key":"e_1_2_8_94_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17036"},{"key":"e_1_2_8_95_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-137-7-200210010-00008"},{"key":"e_1_2_8_96_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-05-1537"},{"key":"e_1_2_8_97_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2033539"},{"key":"e_1_2_8_98_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.19002"},{"key":"e_1_2_8_99_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-022-06391-w"},{"key":"e_1_2_8_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1590-8658(07)80025-9"},{"key":"e_1_2_8_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2011.04.033"},{"key":"e_1_2_8_102_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34331"},{"key":"e_1_2_8_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2015.07.012"},{"key":"e_1_2_8_104_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.190076"},{"key":"e_1_2_8_105_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.07.008"},{"key":"e_1_2_8_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2021.102923"},{"key":"e_1_2_8_107_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.12829"},{"key":"e_1_2_8_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2017.09.005"},{"key":"e_1_2_8_109_1","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000001667"},{"key":"e_1_2_8_110_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2023.199212"},{"key":"e_1_2_8_111_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaf042"},{"issue":"1","key":"e_1_2_8_112_1","first-page":"67","article-title":"HCV\u2010unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian group for the study of cryoglobulinaemias (GISC)","volume":"35","author":"Galli M","year":"2017","journal-title":"Clin Exp Rheumatol."},{"key":"e_1_2_8_113_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-396028"},{"key":"e_1_2_8_114_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lpm.2020.104033"},{"key":"e_1_2_8_115_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-017-1280-6"},{"key":"e_1_2_8_116_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2017.49"},{"issue":"2","key":"e_1_2_8_117_1","first-page":"107","article-title":"Long\u2010term effects of the new direct antiviral agents (DAAs) therapy for HCV\u2010related mixed cryoglobulinaemia without renal involvement: a multicentre open\u2010label study","volume":"36","author":"Mazzaro C","year":"2018","journal-title":"Clin Exp Rheumatol."},{"key":"e_1_2_8_118_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000001239"},{"key":"e_1_2_8_119_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2018.05.021"}],"container-title":["Journal of Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/joim.70042","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T05:00:30Z","timestamp":1768021230000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/joim.70042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":118,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2]]}},"alternative-id":["10.1111\/joim.70042"],"URL":"https:\/\/doi.org\/10.1111\/joim.70042","archive":["Portico"],"relation":{},"ISSN":["0954-6820","1365-2796"],"issn-type":[{"value":"0954-6820","type":"print"},{"value":"1365-2796","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]},"assertion":[{"value":"2025-11-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}