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Successful combination of Rituximab and plasma exchange in the treatment of cryoglobulinemic vasculitis with skin ulcers: a case report



Type II mixed cryoglobulin syndrome is a systematic vasculitis mainly linked to immune complex deposition in several organs and to hepatitis C virus infection. Therapeutic strategies can target either the viral trigger hepatitis C virus if present, or pathogenic events downstream the triggering infection, e.g, the proliferation B-cells directly. Antiviral therapy should be considered as a first-line treatment in many HCV-positive patients. However, it may prove ineffective, contraindicated, or poorly tolerated. The other available treatment [such as cytotoxic agents, steroids] may lead to life-threatening complications and may be difficult to manage in the long term.

Case presentation

We report on a 75-year-old patient with long-lasting hepatitis C virus infection [18 years], a long-lasting cryoglobulinemia [7 years] resistant to common antiviral therapy, diabetes mellitus and deep skin ulcers, successfully treated with the combination therapy of Rituximab and plasma exchange.


Plasma exchange in combination with Rituximab may be useful to heal skin in those patients who are non responsive to Rituximab alone, by avoiding a leg amputation.


Type II mixed cryoglobulinemia (tIIMC ) is a systemic vasculitis caused by immune complexes formed by monoclonal IgM rheumatoid factor and polyclonal IgG [1]. In the large majority of cases, this disorder is caused by chronic hepatitis C virus infection [2]. The immunological mechanism underlying tIIMC consists on the HCV-driven monoclonal expansion of a subset of CD20+, CD27+ memory B-cells expressing a characteristic cross-idiotype [3]. Therefore, the therapy of tIIMC can be focused on inhibition of viral replication or on inhibition of B-cell proliferation. Eradication of HCV infection by antiviral treatment usually leads to the disappearance of cryoglobulins and the regression of vasculitis [4, 5], but several patients are resistant to antiviral therapy or cannot be treated because of side effects or contraindications. Recently, anti B cell therapy with rituximab has been proposed as salvage treatment for patients failing to respond to antiviral therapy [6]-[11]. Rituximab (RTX), a mouse/human chimeric monoclonal anti-CD20 antibody, selectively targets the B-cell compartment from B-cell step to plasma cells, and results in prolonged depletion of normal B-cells from peripheral blood [12]. RTX is approved for the treatment of non-aggressive non-Hodgkin lymphoma [13]. Given the good safety profile and the role of B-cells as antigen-presenting cells or pathogenic antibody producers in many autoimmune disorders, RTX has been used off-label for numerous patients suffering from a great variety of autoimmune diseases [14, 15].Therefore RTX has been successfully employed in tIIMC patients, including HCV-negative and alpha-interferon resistant patients. We report a successful treatment of a patient with cryoglobulinemic vasculitis presenting with skin ulcers, with a combination of rituximab and plasma exchange.

Case presentation

A 75-year-old Caucasian Italian man was admitted because of ulcers on left leg. His past medical history was relevant for a long-lasting (18 years) HCV infection and a long-lasting (7 years) tIIMC resistant to antiviral therapy. He had been undergone an antiviral therapy with a combination of alpha interferon, Ribavirin and prednisolone, with a significant reduction of HCV activity, as demonstrated by a reduction of HCV-RNA levels (800000 UI/L to 13000 UI/L), but without reduction of cryocrit and B-cells (cryocrit 93/μL and B-cells 286/μL). After two years of therapy discontinuation, the patient was admitted at our unit. The HCV activity, cryocrit and B-cell levels were very high (800000 UI/L, 132/μL, 412 B-cells/μl respectively). The leg ulcers measured 8 × 6 cm and 10 × 5 cm and were very aching with signs of infection (Figure 1). We started an antiviral therapy with prednisolone, Interferon-α and Ribavirin which brought to a important reduction of HCV activity (from 800000 UI/L to 54000 UI/L) with slight reduction of cryocrit (132/μL to 112/μL) and B-cells (412/μL to 338/μL). After two weeks of treatment there was no significant improvement in ulcer's healing so we started a therapy with Rituximab. We administered a single course of RTX at a dose of 375 mg/m2 weekly for 4 weeks, and one course of 375 mg/m2 every two months as maintenance regimen. Our patient showed a mild reaction during the first infusion of RTX (mild hypotension and tremor) easily controlled with steroids administration. Treatment with RTX resulted in a slight reduction of cryocrit and B-cells, without significant improvement on ulcer's healing. Finally, the patient underwent five sessions of plasma exchange to reduce cryocrit and a dose of RTX of 375 mg/m2 was administered. This treatment resulted in reduction of cryocrit (2 /μL) and B-cells (205 /μL) and the skin ulcers improved with important reduction of pain. The skin ulcers completely recovered in 6 months (Figure 2).

Figure 1
figure 1

Ulcer to the leg extending to the medial (A) and the anterior (B) part of the foot.

Figure 2
figure 2

Near-complete resolution of the ulcer of the medial part of the foot 4 months after treatment.


Type II mixed cryoglobulinemia is the result of monoclonal IgM paraprotein with rheumatoid activity binding to polyclonal IgG in the circulation, causing immune complexes, complement activation, vasculitis, and gromerulonephritis. tIIMC often is associated with chronic HCV infection.

Patients with a long -lasting tIIMC often are non responders to antiviral therapies. Our patient was unsuccessfully treated with antiviral therapy and Rituximab, and only a combination with RTX and plasma exchange resulted in a clinical improvement. We may speculate that plasma exchange therapy may have removed some immune complexes that can bind part of RTX, and significantly reduced cryocrit and rheumatoid factor, by finally improving the efficacy of Rituximab.


After the failure of RTX the only possibility to kill pain in a patient with skin ulcers is amputation. Plasma exchange in combination with RTX can be useful to heal skin in those patients who are non responsive to RTX alone, by avoiding a leg amputation. The mechanism remains unknown. Further studies will be useful to define if the combination of plasma exchange with RTX can be used in all patients unresponsive to RTX or antiviral therapies.


Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.



Hepatitis C Virus


Immunoglobulin G


Immunoglobulin M




Type II mixed cryoglobulinemia.


  1. Lamprecht P, Moosig F, Gause A, Herlyn K, Csernok E, Hansen H, Gross WL: Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis. 2001, 60: 285-290. 10.1136/ard.60.4.385.

    Article  Google Scholar 

  2. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med. 1992, 327: 1490-1495. 10.1056/NEJM199211193272104.

    Article  CAS  PubMed  Google Scholar 

  3. Carbonari M, Caprini E, Tedesco T, Mazzetta F, Tocco V, Casato M, Russo G, Fiorilli M: Hepatitis C virus drives the unconstrained monoclonal expansion of VH1-69-expression memory B cells in type II cryoglobulinemia: a model of infection-driven lymphomagenesis. J Immunol. 2005, 174: 6532-6539.

    Article  CAS  PubMed  Google Scholar 

  4. Misiani R, Bellavista P, Fenili D, Vicari O, Marchesi D, Sironi PL, Zilio P, Vernocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti A: Interferon alpha-2° therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med. 1994, 330: 751-756. 10.1056/NEJM199403173301104.

    Article  CAS  PubMed  Google Scholar 

  5. Casato M, Agnello V, Pupillo LP, Knight GB, Leoni M, Del Vecchio S, Mazzilli CG, Antonelli G, Bonomo L: Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood. 1997, 90: 3865-3873.

    CAS  PubMed  Google Scholar 

  6. Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F: Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood. 2003, 101: 3818-3826. 10.1182/blood-2002-10-3162.

    Article  CAS  PubMed  Google Scholar 

  7. Zaia F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, Michelutti A, Baccarani M, Fanin R, Ferraccioli G: Efficacy and safety of Rituximab in type II mixed cryoglobulinemia. Blood. 2003, 101: 3827-3834. 10.1182/blood-2002-09-2856.

    Article  Google Scholar 

  8. Lamprecht P, Lerin-Lozano C, Merz H, Dennin RH, Gause A, Voswinkel J, Peters SO, Gutzeit O, Arlt AC, Solbach W, Gross WL: Rituximab induces remission in refractory HCV associated cryoglobulinemic vasculitis. Ann Rheum Dis. 2003, 62: 1230-1233. 10.1136/ard.2002.004929.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Roccatello D, Baldovino S, Rossi D, Mansouri M, Naretto C, Gennaro M, Cavallo R, Alpa M, Costanzo P, Giachino O, Mazzucco G, Sena LM: Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant. 2004, 19: 3054-3061. 10.1093/ndt/gfh469.

    Article  CAS  PubMed  Google Scholar 

  10. Basse G, Ribes D, Kamar N, Mehrenberger M, Esposito L, Guitard J, Lavayssiere L, Oksman F, Durand D, Rostaing L: Rituximab therapy for de novo mixed cryoglobulinemia in renal transplant patients. Transplantation. 2005, 80: 1560-1564. 10.1097/

    Article  CAS  PubMed  Google Scholar 

  11. Quartuccio L, Soardo G, Romano G, Zaja F, Scott CA, De Marchi G, Fabris M, Ferraccioli G, De Vita S: Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinemia: efficacy and safety in the absence of steroids. Rheumatology. 2006, 45: 842-846. 10.1093/rheumatology/kel004.

    Article  CAS  PubMed  Google Scholar 

  12. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR: Depletion of B cells in vivo by chimeric mouse human monoclonal antibody to CD20. Blood. 1994, 83: 435-445.

    CAS  PubMed  Google Scholar 

  13. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R: IDEC-C2B8 [rituximab] anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non Hodgkin lymphoma. Blood. 1997, 90: 2188-2195.

    CAS  PubMed  Google Scholar 

  14. De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G: Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum. 2002, 46: 2029-2033. 10.1002/art.10467.

    Article  CAS  PubMed  Google Scholar 

  15. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004, 350: 2572-2581. 10.1056/NEJMoa032534.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Massimiliano Veroux.

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The authors declare that they have no competing interests'.

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TT was a major contributor in writing the manuscript; MG interpreted the data regarding the follow up of the patient; DC interpreted the laboratory data; GG has been involved in the draft of the manuscript; AG interpreted the data regarding the follow up of the patient; DZ was responsible of the management of the patient; MS was responsible of intensive care management; PV was responsible of the management of the patient; MV was a major contributor in writing the manuscript and has given the final approval to the manuscript

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Tallarita, T., Gagliano, M., Corona, D. et al. Successful combination of Rituximab and plasma exchange in the treatment of cryoglobulinemic vasculitis with skin ulcers: a case report. Cases Journal 2, 7859 (2009).

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