Cryoglobulinemic vasculitis (CryoVas) is an immune complex-mediated inflammation of the small and medium-sized blood vessels, involving complement activation. In 1933, Wintrobe and Buell discovered “cryoprecipitate” in the blood from a patient suffering from multiple myeloma. In 1947, Lerner and Watson coined the term “cryoglobulin” and it applies to immunoglobulins that can precipitate in vitro, from plasma as well as serum when the temperature falls below 37 C and re-solubilize on warming. CryoVas is famously associated with Hepatitis C (Hep-C) as well as some B-cell related blood dyscrasias.
Cryoglobulins can be detectable in the serum of patients with several inflammatory conditions; however, they do not always lead to the disease. The real mechanism of cryoprecipitation is complicated and still not completely understood. It is sometimes attributed to the intrinsic properties of the Immunoglobulin components. Cryoglobulinemic vasculitis can rarely occur by itself and is usually secondary to other diseases. Brouet classified cryoglobulins into 3 major groups based on the immunoglobulin type :
RF activity denotes the binding capacity of IgM to the Fc fragment of IgG. Type 2 and Type 3 are referred to as mixed cryoglobulins. They are commonly associated with infections, autoimmune diseases, and lymphoproliferative disorders:
The prevalence of cryoglobulinemic vasculitis is rare (1:100,000) with significant geographic variations. It is commonly seen in patients aged 45 to 65 years with a maximum incidence in women (sex ratio is 2-3:1). The disease is more common in southern Europe, which might be related to the endemic prevalence of hepatitis C. 20% to 50% of patients with hepatitis C can have serum cryoglobulins; however, only up to one-third of these develop clinical cryoglobulinemic syndrome.
Type 1 cryoglobulins usually cause hyperviscosity syndrome or vasculitis.
Mixed cryoglobulins can be present in normal healthy individuals without causing symptoms. It has been hypothesized that heavy chain glycosylation and other stereotactic properties can influence the activation of complement and Fc receptor of macrophage. There is a role of genetic factors like the presence of BAFF (B-lymphocyte activating factor) and Fc receptor variants, especially in Hepatitis C infected individuals. It is hypothesized that Hepatitis C envelope protein E2 can bind with the B lymphocyte CD81 receptor, thereby acting as an antigenic stimulus. This leads to the formation of antibodies and the resulting antigen-antibody complexes that get deposited in vessel walls. Few cases of sustained vasculitis despite viral clearance indicate that the B cell clones persist despite antigen clearance. It was also observed that B cell-activating factor (BAFF) levels increase despite the completion of antiviral treatment in patients with HCV leading to relapses.
Among type 1 cryoglobulinemic vasculitis, occlusion of vessels can occasionally occur with eosinophilic precipitates. It can be distinguished from fibrin with periodic acid Schiff stain. Leukocytoclastic vasculitis involving the small vessels is the major histopathology in Hep-C associated cutaneous lesions, and vessels from the dermis up to the subcutaneous fat layer can be affected. Immunofluorescence in cryoglobulinemic vasculitis reveals complement and immunoglobulin deposition. The immunoglobulins identified on immunofluorescence vary for each type of cryoglobulinemic vasculitis, for example, in mixed cryoglobulinemic vasculitis, both IgG and IgM deposition along with complements will be seen, while in type I, deposition of a single type of immunoglobulin (most commonly IgM) with complements is seen. Agnello V et al. have demonstrated that the Hep-C virus is concentrated in the cryoprecipitate compared to its presence in the serum. In another study, they have demonstrated the presence of HCV particles in the vascular endothelium of skin lesions.
Membranoproliferative glomerulonephritis is the frequent type of kidney involvement in cryoVas whether or not related to Hep-C. Mesangial proliferative glomerulonephritis and focal proliferative glomerulonephritis are occasionally found. Luminal thrombi in capillary walls have also been seen.
Identification of cryoglobulinemic vasculitis clinically is important because of its potential life-threatening and limb depriving complications.
In mixed cryoglobulinemia, the skin, musculoskeletal system, and kidneys are frequently affected. Historically, Meltzer has described the triad of arthralgias, purpura, and weakness.
Other rare manifestations are:
Baseline complete blood counts, renal function, urinalysis, urine microscopy, and urine protein evaluation (urine protein by creatinine ratio, or 24-hour urine protein) should be performed in all patients with a suspicion of cryoglobulinemic vasculitis. Markers of inflammation, including erythrocyte sedimentation rate and C-reactive protein, may be elevated.
Accurate detection of cryoglobulins can be difficult, and false-positive and false-negative values are not uncommon. The blood shall be drawn into preheated tubes at 37°C until coagulated followed by centrifugation after which, it should be stored at 4°C for 7 days. A white precipitate indicates the presence of cryoglobulins at the bottom of the tube, which dissolves when the tube is rewarmed to 37°C. Quantification of cryoglobulins shall be determined by measuring the percentage of cryoglobulins. Cryoglobulins shall be then characterized by immunologic methods, including immunofixation and immunodiffusion, which help identify the type of immunoglobulin involved. As noted above, false-positive and false-negative test results are common and repeated testing increases accuracy.
Rheumatoid factor testing shall be pursued in all patients with a suspicion of cryoglobulinemic vasculitis. Complement levels shall be tested as well and will usually indicate low serum C4 and normal C3. Serological workup including ANA, Anti-SSA, Anti-SSB, Anti-Ds-DNA, Anti-Smith, and other autoantibodies to detect underlying autoimmune diseases such as systemic lupus erythematosus or Sjogren syndrome shall be considered based on the patient's clinical presentation.
Viral hepatitis screening, including anti-hepatitis C viral antibody, hepatitis C viral RNA PCR, hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody, shall be performed to detect underlying viral hepatitis. Workup for other potential infectious etiology can be considered on an individual basis.
Complete blood count with differential, peripheral smear, flow cytometry for evaluation of underlying leukemia or lymphoma should be considered. Serum protein electrophoresis and quantitative immunoglobulins shall be considered to rule out multiple myeloma or monoclonal gammopathy of unknown significance. Bone marrow or lymph node biopsy may be needed in some cases.
Skin biopsy of cutaneous lesions can be done (and is recommended if initial presentation). Skin biopsy shall be sent for histopathology and for immunofluorescence to identify immune-complexes. In cases of suspicion of renal involvement, renal biopsy shall be considered.
Treatment of cryoglobulinemic vasculitis can require combined inputs from different specialties like hepatologists, rheumatologists, and hematologists, depending on the underlying disease present and the severity of the illness.. The treatment is dictated by the underlying associated etiology, disease severity, and organ involvement. Treatment should be aimed at suppressing B-cell proliferation, eradicating hepatitis C viral infection when present, and reducing circulating immune complex-mediated damage.
In patients with life-threatening or severe manifestations such as mesenteric vasculitis, pulmonary hemorrhage, and rapidly progressing glomerulonephritis, treatment with plasmapheresis and high dose corticosteroids is the first-line therapy. Immunosuppression with rituximab or cyclophosphamide in combination with plasmapheresis and high-dose corticosteroids reduces the risk of relapse. Antiviral therapy for hepatitis C virus is not considered first-line in life-threatening manifestations as the immune process can become independent of viral antigen triggering. Milder manifestations, including skin rash/ulcers, glomerulonephritis, and peripheral neuropathy all respond well to corticosteroids and rituximab with resolution in the symptoms within 6 months of starting rituximab. However, repeat courses of rituximab may be needed to maintain remission. Regimens containing cyclophosphamide and corticosteroids were also tried in this group. Patients who have associated other autoimmune diseases such as systemic lupus erythematosus or Sjogren syndrome also usually respond well to corticosteroids. Immunosuppressive therapy, such as cyclophosphamide for more serious manifestations, methotrexate for milder manifestations, and mycophenolate mofetil for refractory cases, can be used.
In patients with cryoglobulinemic vasculitis associated with hepatitis C infection who have milder manifestation, simultaneous treatment of immunosuppressive therapy, as documented above with antiviral therapy (for hepatitis C viral infection), has been shown to be effective and is the cornerstone of management. Antiviral therapy involving a combination of ribavirin with direct-acting agents like sofosbuvir has shown to be effective. Rituximab, in combination with antiviral therapy involving interferon, seemed to show better clinical outcomes compared to antiviral treatment alone in some trials. Rituximab also showed quicker response rates and better renal relapse rates compared to antiviral therapy alone. It has helped achieve remission in cases where antiviral therapy has failed. Although sustained virologic response seems to correlate well with remission of cryoglobulinemic vasculitis, there are rare instances of persistent cryoglobulins and related symptoms despite viral clearance. This has been attributed to the B cell clonal stimulation, and therefore long term follow-up is essential.
Other Therapeutic Considerations
Cryoglobulinemic vasculitis associated with B-cell dyscrasias and lymphoproliferative diseases can be treated with the disease-specific chemotherapy and occasionally requires immunosuppression. Cyclophosphamide, dexamethasone, and thalidomide can treat cutaneous symptoms (with no renal involvement). Bortezomib has been successfully used to treat cryoglobulinemic vasculitis related to multiple myeloma and MGUS. It was found to be effective in treating patients with concomitant cryoglobulinemic vasculitis and cold agglutinin disease. It was also used in rituximab resistant disease with favorable results. Plasmapheresis is done in life-threatening complications like renal failure or severe cutaneous necrosis.
In patients with cryoglobulinemic vasculitis and hepatitis B infection, treatment with rituximab alone without antiviral therapy can lead to severe reactivation of hepatitis B. It is recommended that antiviral therapy be started before or concomitantly with immunosuppressive therapy (especially rituximab) in these patients.
Other infections causing mixed CryoVas can be treated with specific antimicrobial therapy for sustained remission, immunosuppression is to be used only in refractory cases.
IV immunoglobulin treatment is contraindicated in CryoVas as it can cause immune complex precipitation leading to multi-organ failure.
Systemic lupus erythematosus can cause cutaneous vasculitis, cytopenias, arthralgias, positive RF, and glomerulonephritis. Further, there can be overlap with patients with underlying systemic lupus erythematosus developing cryoglobulinemic vasculitis. Systemic lupus erythematosus is usually associated with low complements, both C3 and C4, and not just isolated C4 depletion. Serum cryoglobulin detection and pathological evaluation are critical in differentiating these two conditions.
Rheumatoid arthritis is associated with joint pain and a positive RF. Rarely, leukocytoclastic vasculitis can be seen in rheumatoid arthritis as well. However, rheumatoid arthritis is associated with the presence of inflammatory arthritis and synovitis, which is usually absent in cryoglobulinemic vasculitis, where patients have arthralgias but usually lacks true synovitis. Further, anti-CCP antibodies are specific for rheumatoid arthritis and are not seen in cryoglobulinemic vasculitis. Renal involvement is rare in rheumatoid arthritis. Complements are usually normal in rheumatoid arthritis. Cryoglobulins will be absent.
Systemic sclerosis can cause cutaneous manifestations like digital ulcers and gangrene. However, other clinical features of systemic sclerosis, including sclerodactyly, calcinosis, interstitial lung disease, gastrointestinal dysmotility, are not seen in cryoglobulinemic vasculitis. Renal involvement in systemic sclerosis is rare and is manifested as scleroderma renal crisis which is different from cryoglobulinemic vasculitis induced glomerulonephritis. Both of these can be differentiated by kidney biopsy.
Henoch Schlein purpura (HSP) causes palpable purpura in lower extremities but can be differentiated by immunofluorescence of skin biopsy. In HSP, immunofluorescence usually shows the deposition of IgA and not immune complexes.
Mortality rates for cryoglobulinemic vasculitis are higher compared to the general population. Most deaths occur due to renal involvement or widespread vasculitis, especially gastrointestinal involvement. The use of antiviral treatment results in better outcomes; however, several poor prognostic factors have been documented.
Poor prognostic features of cryoglobulinemic vasculitis in association with hepatitis C viral infection include:
Poor prognostic features in type 1 cryoglobulinemia are old age and renal involvement. Sign of neuropathy on presentation was also found to be one of the poor prognostic indicators in a retrospective study.
Cryoglobulinemic vasculitis can result in debilitating symptoms like painful neuropathy or complications like gangrene requiring amputations. It is also associated with an increase in mortality and sometimes has many relapses throughout the disease process. Hence it is important to initiate appropriate treatment early in the disease course and have a long term follow up.
Cryoglobulins in the serum can interfere with other lab detection tests like troponin assays and should be kept in mind when there are no clinical features.
A patient with fever, valvular heart disease, negative cultures in the setting of mixed cryoglobulinemia must be evaluated for Q fever.
Although cryoglobulinemic vasculitis is predominantly associated with Hepatitis C virus infection, various specialties are involved in the management of these patients. Gastroenterologists play a role in initiating antiviral therapy along with monitoring the viral load for hepatitis C. Dermatologists are involved when a skin biopsy is needed. The pathologist also plays a role as he could suggest the diagnosis based on labs and biopsies. Rheumatologists are frequently involved in managing severe or resistant cases as they have more experience with immunosuppressive therapies. When cryoglobulinemic vasculitis is related to non-Hepatitis C infections, we need appropriate antibiotic therapy to treat the infection, which may be acting as a trigger. Pharmacists help adjust the doses of medications based on renal function and in monitoring drug interactions. Patients can have complications like multiorgan failure, requiring critical care, and the nursing role is immense in taking care of these patients and in educating the families. Wound care is important as the patients frequently have nonhealing ulcers and gangrene when general surgeons help salvaging the limbs. Hematologists play a major role in treating hematologic malignancies and when complications like lymphoma arise. Primary care physicians play a major role in identifying the disease, as it frequently presents with common outpatient complaints like a purpuric rash, arthralgias, and neuropathic pain. They also play a key role as a mediator between the various specialties, while advocating for the patient and keeping them well-informed. [Level 5]
|||Ferri C, Mixed cryoglobulinemia. Orphanet journal of rare diseases. 2008 Sep 16; [PubMed PMID: 18796155]|
|||LERNER AB,WATSON CJ, Studies of cryoglobulins; unusual purpura associated with the presence of a high concentration of cryoglobulin (cold precipitable serum globulin). The American journal of the medical sciences. 1947 Oct; [PubMed PMID: 20266939]|
|||Middaugh CR,Litman GW, Atypical glycosylation of an IgG monoclonal cryoimmunoglobulin. The Journal of biological chemistry. 1987 Mar 15; [PubMed PMID: 3102493]|
|||Tomana M,Schrohenloher RE,Koopman WJ,Alarcón GS,Paul WA, Abnormal glycosylation of serum IgG from patients with chronic inflammatory diseases. Arthritis and rheumatism. 1988 Mar; [PubMed PMID: 3358797]|
|||Brouet JC,Clauvel JP,Danon F,Klein M,Seligmann M, Biologic and clinical significance of cryoglobulins. A report of 86 cases. The American journal of medicine. 1974 Nov; [PubMed PMID: 4216269]|
|||Terrier B,Karras A,Kahn JE,Le Guenno G,Marie I,Benarous L,Lacraz A,Diot E,Hermine O,de Saint-Martin L,Cathébras P,Leblond V,Modiano P,Léger JM,Mariette X,Senet P,Plaisier E,Saadoun D,Cacoub P, The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine. 2013 Mar; [PubMed PMID: 23429354]|
|||Musset L,Diemert MC,Taibi F,Thi Huong Du L,Cacoub P,Leger JM,Boissy G,Gaillard O,Galli J, Characterization of cryoglobulins by immunoblotting. Clinical chemistry. 1992 Jun; [PubMed PMID: 1597004]|
|||Aguiar MF,Faria-Janes AL,Garcia-Brandes GI,Takemi-Emori C,Ferraz MLG,Andrade LEC,de Souza AWS, Prevalence of cryoglobulinemia and cryoglobulinemic vasculitis in chronically HCV-infected Brazilian patients. Annals of hepatology. 2019 Sep - Oct; [PubMed PMID: 31167733]|
|||Ferri C,Greco F,Longombardo G,Palla P,Moretti A,Marzo E,Fosella PV,Pasero G,Bombardieri S, Antibodies against hepatitis C virus in mixed cryoglobulinemia patients. Infection. 1991 Nov-Dec; [PubMed PMID: 1726164]|
|||Terrier B,Marie I,Lacraz A,Belenotti P,Bonnet F,Chiche L,Graffin B,Hot A,Kahn JE,Michel C,Quemeneur T,de Saint-Martin L,Hermine O,Léger JM,Mariette X,Senet P,Plaisier E,Cacoub P, Non HCV-related infectious cryoglobulinemia vasculitis: Results from the French nationwide CryoVas survey and systematic review of the literature. Journal of autoimmunity. 2015 Dec; [PubMed PMID: 26320984]|
|||Casato M,de Rosa FG,Pucillo LP,Ilardi I,di Vico B,Zorzin LR,Sorgi ML,Fiaschetti P,Coviello R,Laganà B,Fiorilli M, Mixed cryoglobulinemia secondary to visceral Leishmaniasis. Arthritis and rheumatism. 1999 Sep; [PubMed PMID: 10513819]|
|||Galli M,Invernizzi F,Chemotti M,Monti G,Gasparro MG,Caredda F,Negri C,Moroni M, Cryoglobulins and infectious diseases. La Ricerca in clinica e in laboratorio. 1986 Apr-Jun; [PubMed PMID: 3097790]|
|||Lazzerini PE,Cusi MG,Selvi E,Capecchi M,Moscadelli V,Migliacci N,Finizola F,Laghi-Pasini F, Non-HCV-related cryoglobulinemic vasculitis and parvovirus-B19 infection. Joint bone spine. 2018 Jan; [PubMed PMID: 28062379]|
|||Hasegawa J,Hayami N,Hoshino J,Suwabe T,Sumida K,Mise K,Ueno T,Yamanouchi M,Sawa N,Ohashi K,Fujii T,Takaichi K,Ubara Y, Cryoglobulinemic vasculitis with primary Sjögren's syndrome: A case report. Modern rheumatology. 2018 May; [PubMed PMID: 26743943]|
|||Giuggioli D,Manfredi A,Colaci M,Manzini CU,Antonelli A,Ferri C, Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of the literature. Autoimmunity reviews. 2013 Sep; [PubMed PMID: 23806565]|
|||Horino T,Hamada-Ode K,Ichii O,Terada Y, Overlapping Syndrome of Systemic Scleroderma and Cryoglobulinemic Vasculitis. The American journal of medicine. 2019 Jun; [PubMed PMID: 30831066]|
|||Nozawa K,Kaneko H,Itoh T,Katsura Y,Noguchi M,Suzuki F,Takasaki Y,Ogawa H,Takamori K,Sekigawa I, Synchronous malignant B-cell lymphoma and gastric tubular adenocarcinoma associated with paraneoplastic cutaneous vasculitis: hypereosinophilic syndrome with mixed cryoglobulinemia is an important sign of paraneoplastic syndrome. Rare tumors. 2009 Dec 28; [PubMed PMID: 21139921]|
|||Ferri C,Zignego AL,Pileri SA, Cryoglobulins. Journal of clinical pathology. 2002 Jan; [PubMed PMID: 11825916]|
|||Ramos-Casals M,Muñoz S,Medina F,Jara LJ,Rosas J,Calvo-Alen J,Brito-Zerón P,Forns X,Sánchez-Tapias JM, Systemic autoimmune diseases in patients with hepatitis C virus infection: characterization of 1020 cases (The HISPAMEC Registry). The Journal of rheumatology. 2009 Jul; [PubMed PMID: 19369460]|
|||Gatta A,Giannini C,Lampertico P,Pontisso P,Quarta S,Zignego AL,Atzeni F,Sarzi-Puttini P, Hepatotropic viruses: new insights in pathogenesis and treatment. Clinical and experimental rheumatology. 2008 Jan-Feb; [PubMed PMID: 18570752]|
|||Payet J,Livartowski J,Kavian N,Chandesris O,Dupin N,Wallet N,Karras A,Salliot C,Suarez F,Avet-Loiseau H,Alyanakian MA,Nawakil CA,Park S,Tamburini J,Roux C,Bouscary D,Sparsa L, Type I cryoglobulinemia in multiple myeloma, a rare entity: analysis of clinical and biological characteristics of seven cases and review of the literature. Leukemia [PubMed PMID: 22385269]|
|||Pawlotsky JM,Ben Yahia M,Andre C,Voisin MC,Intrator L,Roudot-Thoraval F,Deforges L,Duvoux C,Zafrani ES,Duval J, Immunological disorders in C virus chronic active hepatitis: a prospective case-control study. Hepatology (Baltimore, Md.). 1994 Apr; [PubMed PMID: 8138255]|
|||Strait RT,Posgai MT,Mahler A,Barasa N,Jacob CO,Köhl J,Ehlers M,Stringer K,Shanmukhappa SK,Witte D,Hossain MM,Khodoun M,Herr AB,Finkelman FD, IgG1 protects against renal disease in a mouse model of cryoglobulinaemia. Nature. 2015 Jan 22; [PubMed PMID: 25363774]|
|||Gragnani L,Piluso A,Giannini C,Caini P,Fognani E,Monti M,Petrarca A,Ranieri J,Razzolini G,Froio V,Laffi G,Zignego AL, Genetic determinants in hepatitis C virus-associated mixed cryoglobulinemia: role of polymorphic variants of BAFF promoter and Fcγ receptors. Arthritis and rheumatism. 2011 May; [PubMed PMID: 21538321]|
|||Sansonno D,Cornacchiulo V,Iacobelli AR,Di Stefano R,Lospalluti M,Dammacco F, Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. Hepatology (Baltimore, Md.). 1995 Feb; [PubMed PMID: 7843698]|
|||Ferri C,Mascia MT, Cryoglobulinemic vasculitis. Current opinion in rheumatology. 2006 Jan; [PubMed PMID: 16344620]|
|||Levine JW,Gota C,Fessler BJ,Calabrese LH,Cooper SM, Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. The Journal of rheumatology. 2005 Jun; [PubMed PMID: 15940780]|
|||Landau DA,Saadoun D,Halfon P,Martinot-Peignoux M,Marcellin P,Fois E,Cacoub P, Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis and rheumatism. 2008 Feb; [PubMed PMID: 18240235]|
|||Berera S,Gomez A,Dholaria K,Arosemena LR,Ladino-Avellaneda MA,Barisoni L,Bhamidimarri KR, A Rare Case of Hepatitis C-Associated Cryoglobulinemic Duodenal Vasculitis. ACG case reports journal. 2016 Aug; [PubMed PMID: 27807586]|
|||Bonacci M,Lens S,Mariño Z,Londoño MC,Rodriguez-Tajes S,Sánchez-Tapias JM,Ramos-Casals M,Hernández-Rodríguez J,Forns X, Long-Term Outcomes of Patients With HCV-Associated Cryoglobulinemic Vasculitis After Virologic Cure. Gastroenterology. 2018 Aug; [PubMed PMID: 29705529]|
|||Visentini M,Fiorilli M,Casato M, Persistence of Pathogenic B-Cell Clones and Relapse of Cryoglobulinemic Vasculitis in HCV-Cured Patients. Gastroenterology. 2019 Jan; [PubMed PMID: 30315773]|
|||Hegazy MT,Allam WR,Hussein MA,Zoheir N,Quartuccio L,El-Khamisy SF,Ragab G, Increased genomic instability following treatment with direct acting anti-hepatitis C virus drugs. EBioMedicine. 2018 Sep; [PubMed PMID: 30139628]|
|||Kazandjieva J,Antonov D,Kamarashev J,Tsankov N, Acrally distributed dermatoses: Vascular dermatoses (purpura and vasculitis). Clinics in dermatology. 2017 Jan - Feb; [PubMed PMID: 27938815]|
|||Agnello V,Chung RT,Kaplan LM, A role for hepatitis C virus infection in type II cryoglobulinemia. The New England journal of medicine. 1992 Nov 19; [PubMed PMID: 1383822]|
|||Agnello V,Abel G, Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis and rheumatism. 1997 Nov; [PubMed PMID: 9365090]|
|||Spatola L,Generali E,Angelini C,Badalamenti S,Selmi C, HCV-negative mixed cryoglobulinemia and kidney involvement: in-depth review on physiopathological and histological bases. Clinical and experimental medicine. 2018 Nov; [PubMed PMID: 29956004]|
|||Matignon M,Cacoub P,Colombat M,Saadoun D,Brocheriou I,Mougenot B,Roudot-Thoraval F,Vanhille P,Moranne O,Hachulla E,Hatron PY,Fermand JP,Fakhouri F,Ronco P,Plaisier E,Grimbert P, Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection. Medicine. 2009 Nov; [PubMed PMID: 19910748]|
|||Retamozo S,Díaz-Lagares C,Bosch X,Bové A,Brito-Zerón P,Gómez ME,Yagüe J,Forns X,Cid MC,Ramos-Casals M, Life-Threatening Cryoglobulinemic Patients With Hepatitis C: Clinical Description and Outcome of 279 Patients. Medicine. 2013 Sep; [PubMed PMID: 23974248]|
|||Martin-Bouyer G, [Data concerning venereal diseases in metropolitan France for the year 1966]. Bulletin de l'Institut national de la sante et de la recherche medicale. 1967 Sep-Oct; [PubMed PMID: 5632353]|
|||Sanmugarajah J,Hussain S,Schwartz JM,Friedman S, Monoclonal cryoglobulinemia with extensive gangrene of all four extremities--a case report. Angiology. 2000 May; [PubMed PMID: 10826861]|
|||Meltzer M,Franklin EC,Elias K,McCluskey RT,Cooper N, Cryoglobulinemia--a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. The American journal of medicine. 1966 Jun; [PubMed PMID: 4956871]|
|||Ferri C,Sebastiani M,Giuggioli D,Cazzato M,Longombardo G,Antonelli A,Puccini R,Michelassi C,Zignego AL, Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Seminars in arthritis and rheumatism. 2004 Jun; [PubMed PMID: 15190522]|
|||Ammendola A,Sampaolo S,Ambrosone L,Ammendola E,Ciccone G,Migliaresi S,Di Iorio G, Peripheral neuropathy in hepatitis-related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle [PubMed PMID: 15515001]|
|||Cacoub P,Saadoun D,Limal N,Léger JM,Maisonobe T, Hepatitis C virus infection and mixed cryoglobulinaemia vasculitis: a review of neurological complications. AIDS (London, England). 2005 Oct; [PubMed PMID: 16251808]|
|||Casato M,Saadoun D,Marchetti A,Limal N,Picq C,Pantano P,Galanaud D,Cianci R,Duhaut P,Piette JC,Fiorilli M,Cacoub P, Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsychological tests. The Journal of rheumatology. 2005 Mar; [PubMed PMID: 15742440]|
|||Cavalli G,Berti A,Fragasso G,De Cobelli F, Hypertrophic cardiomyopathy secondary to hepatitis C virus-related vasculitis. Journal of cardiovascular medicine (Hagerstown, Md.). 2016 Dec; [PubMed PMID: 24979124]|
|||De Vita S, Treatment of mixed cryoglobulinemia: a rheumatology perspective. Clinical and experimental rheumatology. 2011 Jan-Feb; [PubMed PMID: 21586203]|
|||Terrier B,Krastinova E,Marie I,Launay D,Lacraz A,Belenotti P,de Saint-Martin L,Quemeneur T,Huart A,Bonnet F,Le Guenno G,Kahn JE,Hinschberger O,Rullier P,Diot E,Lazaro E,Bridoux F,Zénone T,Carrat F,Hermine O,Léger JM,Mariette X,Senet P,Plaisier E,Cacoub P, Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012 Jun 21; [PubMed PMID: 22474249]|
|||Koukoulaki M,Abeygunasekara SC,Smith KG,Jayne DR, Remission of refractory hepatitis C-negative cryoglobulinaemic vasculitis after rituximab and infliximab. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2005 Jan; [PubMed PMID: 15632353]|
|||Mukhtyar C,Guillevin L,Cid MC,Dasgupta B,de Groot K,Gross W,Hauser T,Hellmich B,Jayne D,Kallenberg CG,Merkel PA,Raspe H,Salvarani C,Scott DG,Stegeman C,Watts R,Westman K,Witter J,Yazici H,Luqmani R, EULAR recommendations for the management of primary small and medium vessel vasculitis. Annals of the rheumatic diseases. 2009 Mar; [PubMed PMID: 18413444]|
|||Ostojic P, Cryoglobulinemic vasculitis in systemic sclerosis successfully treated with mycophenolate mofetil. Rheumatology international. 2014 Jan; [PubMed PMID: 23271426]|
|||Cacoub P,Si Ahmed SN,Ferfar Y,Pol S,Thabut D,Hezode C,Alric L,Comarmond C,Ragab G,Quartuccio L,Hegazy M,Poynard T,Resche Rigon M,Saadoun D, Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinemia Vasculitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019 Feb; [PubMed PMID: 29857143]|
|||Saadoun D,Thibault V,Si Ahmed SN,Alric L,Mallet M,Guillaud C,Izzedine H,Plaisier A,Fontaine H,Costopoulos M,Le Garff-Tavernier M,Hezode C,Pol S,Musset L,Poynard T,Cacoub P, Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Annals of the rheumatic diseases. 2016 Oct; [PubMed PMID: 26567178]|
|||Taha R,El-Haddad H,Almuallim A,Alshaiki F,Obaid E,Almoallim H, Systematic review of the role of rituximab in treatment of antineutrophil cytoplasmic autoantibody-associated vasculitis, hepatitis C virus-related cryoglobulinemic vasculitis, Henoch-Schönlein purpura, ankylosing spondylitis, and Raynaud's phenomenon. Open access rheumatology : research and reviews. 2017; [PubMed PMID: 29290695]|
|||Dammacco F,Tucci FA,Lauletta G,Gatti P,De Re V,Conteduca V,Sansonno S,Russi S,Mariggiò MA,Chironna M,Sansonno D, Pegylated interferon-alpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: a long-term study. Blood. 2010 Jul 22; [PubMed PMID: 20308602]|
|||Saadoun D,Resche Rigon M,Sene D,Terrier B,Karras A,Perard L,Schoindre Y,Coppéré B,Blanc F,Musset L,Piette JC,Rosenzwajg M,Cacoub P, Rituximab plus Peg-interferon-alpha/ribavirin compared with Peg-interferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood. 2010 Jul 22; [PubMed PMID: 20439619]|
|||Sneller MC,Hu Z,Langford CA, A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis and rheumatism. 2012 Mar; [PubMed PMID: 22147444]|
|||De Vita S,Quartuccio L,Isola M,Mazzaro C,Scaini P,Lenzi M,Campanini M,Naclerio C,Tavoni A,Pietrogrande M,Ferri C,Mascia MT,Masolini P,Zabotti A,Maset M,Roccatello D,Zignego AL,Pioltelli P,Gabrielli A,Filippini D,Perrella O,Migliaresi S,Galli M,Bombardieri S,Monti G, A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis and rheumatism. 2012 Mar; [PubMed PMID: 22147661]|
|||Sise ME,Bloom AK,Wisocky J,Lin MV,Gustafson JL,Lundquist AL,Steele D,Thiim M,Williams WW,Hashemi N,Kim AY,Thadhani R,Chung RT, Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology (Baltimore, Md.). 2016 Feb; [PubMed PMID: 26474537]|
|||Wen J,Xu F,Li M,Zhou Q,Qu W,Liu Y,Su J,Hu H, Type I cryoglobulinemic vasulitis with eosinophilia: A case report and literature review. Medicine. 2019 Jul; [PubMed PMID: 31305439]|
|||Ramirez GA,Campochiaro C,Salmaggi C,Pagliula G,D'Aliberti T,Marcatti M,Tresoldi M,Praderio L, Bortezomib in type I cryoglobulinemic vasculitis: are we acting too late? Internal medicine (Tokyo, Japan). 2015; [PubMed PMID: 25948361]|
|||Liu XH,Liu MX,Jin F,Zhang M,Zhang L, Concomitant cryoglobulinemic vasculitis and cold agglutinin disease successfully treated with bortezomib: A case report. Medicine. 2019 Jan; [PubMed PMID: 30681592]|
|||Spizzo G,Mitterer M,Gunsilius E, Bortezomib for the treatment of refractory Type-1 cryoglobulinaemia. British journal of haematology. 2010 Jul; [PubMed PMID: 20346005]|
|||Mazzaro C,Dal Maso L,Urraro T,Mauro E,Castelnovo L,Casarin P,Monti G,Gattei V,Zignego AL,Pozzato G, Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie - GISC. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2016 Jul; [PubMed PMID: 27106525]|
|||Pasquet F,Combarnous F,Macgregor B,Coppere B,Mausservey C,Ninet J,Hot A, Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report. Journal of medical case reports. 2012 Jan 27; [PubMed PMID: 22284897]|
|||Oykhman P,Hamilton MA,Aaron SL, Multiorgan Failure From Cryoglobulinemic Vasculitis Following Intravenous Immunoglobulin Replacement Therapy. Journal of clinical rheumatology : practical reports on rheumatic [PubMed PMID: 27870771]|
|||Chandesris MO,Gayet S,Schleinitz N,Doudier B,Harlé JR,Kaplanski G, Infliximab in the treatment of refractory vasculitis secondary to hepatitis C-associated mixed cryoglobulinaemia. Rheumatology (Oxford, England). 2004 Apr; [PubMed PMID: 15024144]|
|||Bartolucci P,Ramanoelina J,Cohen P,Mahr A,Godmer P,Le Hello C,Guillevin L, Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford, England). 2002 Oct; [PubMed PMID: 12364631]|
|||Della Rossa A,Marchi F,Catarsi E,Tavoni A,Bombardieri S, Mixed cryoglobulinemia and mortality: a review of the literature. Clinical and experimental rheumatology. 2008 Sep-Oct; [PubMed PMID: 19026151]|
|||Guillevin L,Lhote F,Gayraud M,Cohen P,Jarrousse B,Lortholary O,Thibult N,Casassus P, Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine. 1996 Jan; [PubMed PMID: 8569467]|
|||Terrier B,Semoun O,Saadoun D,Sène D,Resche-Rigon M,Cacoub P, Prognostic factors in patients with hepatitis C virus infection and systemic vasculitis. Arthritis and rheumatism. 2011 Jun; [PubMed PMID: 21400476]|
|||Calle Toro JS,Davalos DM,Charry JD,Arrunategi AM,Tobon G, Hepatic and Mesenteric Vasculitis as Presenting Manifestation of Mixed Cryoglobulinemia Related to Chronic Hepatitis C Virus Infection in a Female Patient. Journal of clinical rheumatology : practical reports on rheumatic [PubMed PMID: 27219310]|
|||Terrier B,Carrat F,Krastinova E,Marie I,Launay D,Lacraz A,Belenotti P,de Saint Martin L,Quemeneur T,Huart A,Bonnet F,Le Guenno G,Kahn JE,Hinschberger O,Rullier P,Hummel A,Diot E,Pagnoux C,Lzaro E,Bridoux F,Zenone T,Hermine O,Leger JM,Mariette X,Senet P,Plaisier E,Cacoub P, Prognostic factors of survival in patients with non-infectious mixed cryoglobulinaemia vasculitis: data from 242 cases included in the CryoVas survey. Annals of the rheumatic diseases. 2013 Mar; [PubMed PMID: 22586172]|
|||Zaidan M,Terrier B,Pozdzik A,Frouget T,Rioux-Leclercq N,Combe C,Lepreux S,Hummel A,Noël LH,Marie I,Legallicier B,François A,Huart A,Launay D,Kaplanski G,Bridoux F,Vanhille P,Makdassi R,Augusto JF,Rouvier P,Karras A,Jouanneau C,Verpont MC,Callard P,Carrat F,Hermine O,Léger JM,Mariette X,Senet P,Saadoun D,Ronco P,Brochériou I,Cacoub P,Plaisier E, Spectrum and Prognosis of Noninfectious Renal Mixed Cryoglobulinemic GN. Journal of the American Society of Nephrology : JASN. 2016 Apr; [PubMed PMID: 26260165]|
|||Sidana S,Rajkumar SV,Dispenzieri A,Lacy MQ,Gertz MA,Buadi FK,Hayman SR,Dingli D,Kapoor P,Gonsalves WI,Go RS,Hwa YL,Leung N,Fonder AL,Hobbs MA,Zeldenrust SR,Russell SJ,Lust JA,Kyle RA,Kumar SK, Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. American journal of hematology. 2017 Jul; [PubMed PMID: 28370486]|
|||Monti G,Pioltelli P,Saccardo F,Campanini M,Candela M,Cavallero G,De Vita S,Ferri C,Mazzaro C,Migliaresi S,Ossi E,Pietrogrande M,Gabrielli A,Galli M,Invernizzi F, Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Archives of internal medicine. 2005 Jan 10; [PubMed PMID: 15642884]|
|||Arandjelovic S,Bonaci-Nikolic B,Peric-Popadic A,Tomic-Spiric V,Bolpacic J,Raskovic S,Andrejevic S, HCV related severe cryoglobulinemic vasculitis treated with plasma exchange and rituximab: case report and literature review. Journal of infection in developing countries. 2017 Jun 1; [PubMed PMID: 30943182]|
|||Odish M,Beben T,Daniels LB, False-positive Troponin I Assay elevation due to occult Mixed Cryoglobulinemic Vasculitis. Reviews in cardiovascular medicine. 2018 Jun 30; [PubMed PMID: 31032606]|