Skip to main content
SpringerLink
Log in

Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis

  • Original Article
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

This study aims to evaluate the efficacy and safety of repeated treatments with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Thirty-seven patients with mixed cryoglobulinemia vasculitis refractory to standard of care treatment, 34 of which were HCV-positive, were treated with rituximab at the reduced dosage of 250 mg/m2 given twice 1 week apart per cycle. Thirty patients (81%) achieved a clinical response; 5 of them remain in remission, 3 were lost to follow-up or died, and 22 relapsed after a mean of 15.7 months. Eleven relapsers were retreated with one (6 patients), 2 (3 patients), or 3 (2 patients) additional rituximab cycles given at each relapse. Clinical and laboratory efficacy and side effects of long-term treatment were evaluated. Clinical response to retreatment was 91% (10/11) at the first relapse, 80% (4/5) at the second relapse, and 100% (2/2) at the third relapse. The mean (±SD) time to relapse was 17.1 ± 14.1 months in 30 patients who were treated with only one cycle (from first cycle to the first relapse) and 45.7 ± 30.6 months (from first cycle to the last observed relapse) in 11 patients treated with 2 or more cycles (p = 0.0037). Severe adverse reactions occurred in 3 patients, in 2 of whom at the first cycle. Our results suggest that repeated treatment of relapsing mixed cryoglobulinemia with a low-dose rituximab regimen is efficacious, safe, and cost-effective for the long-term management of this disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Cacoub P, Comarmond C, Domont F, Savey L, Saadoun D (2015) Cryoglobulinemia vasculitis. Am J Med 128:950–955

    Article  PubMed  Google Scholar 

  2. Damoiseaux J (2014) The diagnosis and classification of the cryoglobulinemic syndrome. Autoimmun Rev 13:359–362

    Article  CAS  PubMed  Google Scholar 

  3. Ferri C, Ramos-Casals M, Zignego AL, Arcaini L, Roccatello D, Antonelli A, Saadoun D, Desbois AC, Sebastiani M, Casato M, Lamprecht P, Mangia A, Tzioufas AG, Younossi ZM, Cacoub P (2016) ISG-EHCV coauthors International diagnostic guidelines for patients with HCV-related extrahepatic manifestations. A multidisciplinary expert statement. Autoimmun Rev 15:1145–1160

  4. Zignego AL, Wojcik GL, Cacoub P, Visentini M, Casato M, Mangia A, Latanich R, Charles ED, Gragnani L, Terrier B, Piazzola V, Dustin LB, Khakoo SI, Busch MP, Lauer GM, Kim AY, Alric L, Thomas DL, Duggal P (2014) Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis. Genes Immun 15:500–505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette JC, Opolon P (1999) Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC group. Multidepartment virus C. Arthritis Rheum 42:2204–2212

    Article  CAS  PubMed  Google Scholar 

  6. Trejo O, Ramos-Casals M, García-Carrasco M, Yagüe J, Jiménez S, de la Red G, Cervera R, Font J, Ingelmo M (2001) Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore) 80:252–262

    Article  CAS  Google Scholar 

  7. Saadoun D, Sellam J, Ghillani-Dalbin P, Crecel R, Piette JC, Cacoub P (2006) Increased risks of lymphoma and death among patients with non-hepatitis C virus-related mixed cryoglobulinemia. Arch Intern Med 166:2101–2108

    Article  PubMed  Google Scholar 

  8. Ferri C, Zignego AL, Pileri SA (2002) Cryoglobulins. J Clin Pathol 55:4–13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Monti G, Saccardo F, Castelnovo L, Novati P, Sollima S, Riva A, Sarzi-Puttini P, Quartuccio L, De Vita S, Galli M (2014) Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study. Autoimmun Rev 13:609–614

    Article  CAS  PubMed  Google Scholar 

  10. Dammacco F, Sansonno D (2013) Therapy for hepatitis C virus-related cryoglobulinemic vasculitis. N Engl J Med 369:1035–1045

    Article  CAS  PubMed  Google Scholar 

  11. Pietrogrande M, De Vita S, Zignego AL, Pioltelli P, Sansonno D, Sollima S, Atzeni F, Saccardo F, Quartuccio L, Bruno S, Bruno R, Campanini M, Candela M, Castelnovo L, Gabrielli A, Gaeta GB, Marson P, Mascia MT, Mazzaro C, Mazzotta F, Meroni P, Montecucco C, Ossi E, Piccinino F, Prati D, Puoti M, Riboldi P, Riva A, Roccatello D, Sagnelli E, Scaini P, Scarpato S, Sinico R, Taliani G, Tavoni A, Bonacci E, Renoldi P, Filippini D, Sarzi-Puttini P, Ferri C, Monti G, Galli M (2011) Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev 10:444–454

    Article  PubMed  Google Scholar 

  12. Gragnani L, Fognani E, Piluso A, Boldrini B, Urraro T, Fabbrizzi A, Stasi C, Ranieri J, Monti M, Arena U, Iannacone C, Laffi G, Zignego AL, MaSVE Study Group (2015) Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study. Hepatology 61:1145–1153

    Article  CAS  PubMed  Google Scholar 

  13. Gragnani L, Visentini M, Fognani E, Urraro T, De Santis A, Petraccia L, Perez M, Ceccotti G, Colantuono S, Mitrevski M, Stasi C, Del Padre M, Monti M, Gianni E, Pulsoni A, Fiorilli M, Casato M, Zignego AL (2016) Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. Hepatology 64:1473–1482

    Article  CAS  PubMed  Google Scholar 

  14. Ferri C, Cacoub P, Mazzaro C, Roccatello D, Scaini P, Sebastiani M, Tavoni A, Zignego AL, De Vita S (2011) Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev 11:48–55

    Article  CAS  PubMed  Google Scholar 

  15. Visentini M, Ludovisi S, Petrarca A, Pulvirenti F, Zaramella M, Monti M, Conti V, Ranieri J, Colantuono S, Fognani E, Piluso A, Tinelli C, Zignego AL, Mondelli MU, Fiorilli M, Casato M (2011) A phase II, single-arm multicenter study of low-dose rituximab for refractory mixed cryoglobulinemia secondary to hepatitis C virus infection. Autoimmun Rev 10:714–719

    Article  CAS  PubMed  Google Scholar 

  16. 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 (2012) A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 64:843–853

    Article  CAS  PubMed  Google Scholar 

  17. Sneller MC, Hu Z, Langford CA (2012) A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 64:835–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Visentini M, Tinelli C, Colantuono S, Monti M, Ludovisi S, Gragnani L, Mitrevski M, Ranieri J, Fognani E, Piluso A, Granata M, De Silvestri A, Scotti V, Mondelli MU, Zignego AL, Fiorilli M, Casato M (2015) Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: phase II clinical trial and systematic review. Autoimmun Rev 4:889–896

    Article  Google Scholar 

  19. Wink F, Houtman PM, Jansen TL (2011) Rituximab in cryoglobulinaemic vasculitis, evidence for its effectivity: a case report and review of literature. Clin Rheumatol 30:293–300

    Article  PubMed  Google Scholar 

  20. Terrier B, Launay D, Kaplanski G, Hot A, Larroche C, Cathébras P, Combe B, de Jaureguiberry JP, Meyer O, Schaeverbeke T, Somogyi A, Tricot L, Zénone T, Ravaud P, Gottenberg JE, Mariette X, Cacoub P (2010) Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French autoimmunity and rituximab registry. Arthritis Care Res (Hoboken) 62:1787–1795

    Article  CAS  Google Scholar 

  21. Foessel L, Besancenot JF, Blaison G, Magy-Bertrand N, Jaussaud R, Etienne Y, Maurier F, Audia S, Martin T (2011) Clinical spectrum, treatment, and outcome of patients with type II mixed cryoglobulinemia without evidence of hepatitis C infection. J Rheumatol 38:716–722

    Article  PubMed  Google Scholar 

  22. 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 (2012) Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood 119:5996–6004

    Article  CAS  PubMed  Google Scholar 

  23. Terrier B, 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 (2014) Predictors of early relapse in patients with non-infectious mixed cryoglobulinemia vasculitis: results from the French nationwide CryoVas survey. Autoimmun Rev 13:630–634

    Article  CAS  PubMed  Google Scholar 

  24. Quartuccio L, Zuliani F, Corazza L, Scaini P, Zani R, Lenzi M, Tavoni A, Sebastiani M, Baldovino S, Urraro T, Saccardo F, Sbreglia C, Mazzaro C, Pioltelli P, Fraticelli P, Filippini D, Gabrielli A, Perrella O, Scarpato S, Roccatello D, Zignego AL, Ferri C, Bombardieri S, Pietrogrande M, Monti G, Galli M, De Vita S (2015) Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: long-term follow up data of a randomized controlled multicentre study. J Autoimmun 63:88–93

    Article  CAS  PubMed  Google Scholar 

  25. Roccatello D, Sciascia S, Baldovino S, Rossi D, Alpa M, Naretto C, Di Simone D, Menegatti E (2016) Improved (4 plus 2) rituximab protocol for severe cases of mixed cryoglobulinemia: a 6-year observational study. Am J Nephrol 43:251–260

    Article  CAS  PubMed  Google Scholar 

  26. Bianchettin G, Bonaccini C, Oliva R, Tramontano A, Cividini A, Casato M, Merlini G, Silini E, Mondelli MU (2007) Analysis of hepatitis C virus hypervariable region 1 sequence from cryoglobulinemic patients and associated controls. J Virol 81:4564–4571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB (2015) Longterm safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years. J Rheumatol 42:1761–1766

    Article  PubMed  Google Scholar 

  28. Webster DP, Klenerman P, Dusheiko GM (2015) Hepatitis C. Lancet 385:1124–1135

    Article  PubMed  PubMed Central  Google Scholar 

  29. Arcaini L, Besson C, Frigeni M, Fontaine H, Goldaniga M, Casato M, Visentini M, Torres HA, Loustaud-Ratti V, Peveling-Oberhag J, Fabris P, Rossotti R, Zaja F, Rigacci L, Rattotti S, Bruno R, Merli M, Dorival C, Alric L, Jaccard A, Pol S, Carrat F, Ferretti VV, Visco C, Hermine O (2016) Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Blood 128:2527–2432

    Article  CAS  PubMed  Google Scholar 

  30. Urraro T, Gragnani L, Piluso A, Fabbrizzi A, Monti M, Fognani E, Boldrini B, Ranieri J, Zignego AL (2015) Combined treatment with antiviral therapy and rituximab in patients with mixed cryoglobulinemia: review of the literature and report of a case using direct antiviral agents-based antihepatitis C virus therapy. Case Reports Immunol 2015:816424

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Italian Medicines Agency [grant number FARM6KMZFY]. Marcella Visentini was supported by Fondazione Roma, Rome, Italy [Prot.287/AI].

Author information

Authors and Affiliations

  1. Department of Clinical Medicine, Sapienza University of Rome, Viale dell’Università 37, 00185, Rome, Italy

    Stefania Colantuono, Milica Mitrevski, Baoran Yang, Julia Tola, Maurizio Carlesimo, Massimo Fiorilli, Milvia Casato & Marcella Visentini

  2. Department of Infectious Diseases, Sapienza University of Rome, Rome, Italy

    Giuseppe M. De Sanctis

Authors
  1. Stefania Colantuono
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Milica Mitrevski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baoran Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julia Tola
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maurizio Carlesimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giuseppe M. De Sanctis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Massimo Fiorilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Milvia Casato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcella Visentini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcella Visentini.

Ethics declarations

This study was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practices and was approved by the ethical body of the Policlinico Umberto I, Sapienza University of Rome (ethics approval number 1397/10.04.08).

Informed consent

All patients provided written informed consent to treatment.

Disclosures

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Colantuono, S., Mitrevski, M., Yang, B. et al. Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Clin Rheumatol 36, 617–623 (2017). https://doi.org/10.1007/s10067-017-3552-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-017-3552-6

Keywords

Search

Navigation