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elisia
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| Posted: November 11 2008 at 12:59pm
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| November, 2008 - CRA Journal Club: Review by Dr. ANDY THOMPSON |
Rituximab combined with Peg-Interferon-Ribavirin in refractory HCV-associated cryoglobulinemia vasculitis.
Saadoun D, Resche-Rigon M, Sene D, Perard L, Piette JC, Cacoub P - Ann Rheum Dis, Oct 2008; 67: 1431 - 1436.
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Director of Post-Graduate Education
Assistant Professor of Medicine
Division of Rheumatology, Dept of Medicine
Schulich School of Medicine U.of Western ON
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Learning Objectives:
- Understand the utility of rituximab in the management of cryoglobulinemic vasculitis
- Realize the existence of a growing body of evidence for this therapy
Cryoglubulinemia is defined as the presence of one or more immunoglobulins which precipitate at temperatures below 37 degrees and re-dissolve on rewarming. Rheumatologists are well aware that cryoglobulins can take the form of a monoclonal antibody (type 1) or an immune complex containing IgM and IgG (Type 2 & 3). Cryoglobulinemic vasculitis is thought to be secondary to vascular deposition of circulating immune complexes and complement.
The association between mixed cryoglobulinemia (mc) and hepatitis C (HCV) infection was firmly established in 1991 when 86% of Italian MC patients were found to have anti-HCV.1 Chronic HCV infection can stimulate poly-oligoclonal B-cell expansion resulting in the production of various autoantibodies (rheumatoid factor, circulating-immune complexes, and mixed cryoglobulinemia).
Treatment of HCV related mixed cryoglobulinemia (HCV-MC) remains challenging. Although anti-viral therapy can result in sustained clinical and virological responses, treatment of severe life and organ threatening involvement usually requires corticosteroids and immunosuppressants. There is a mounting body of evidence that targeted B-cell depletion therapy with anti-CD20 (rituximab) is very effective against cryoglobulin production and its consequences.1-8 This study examines the effects of rituximab therapy combined with interferon & ribavirin therapy for HCV-MC.
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Study Design: This was a pilot study of sixteen patients with HCV-MC who were resistant (n=11) or relapser (n=5) to interferon or pegylated-interferon plus ribavirin. The inclusion criteria were: (a) chronic HCV infection; (b) severe organ involvement due to MC; (c) previous non-responder or relapser; and (d) Greater than 6 months since last anti-HCV treatment. All patients had histologically confirmed vasculitis and none had received rituximab or cyclophosphamide. The treatment schedule consisted of the weekly administration of four intravenous infusions of rituximab at 375 mg/m2 (on days +1, +8, +15, +22) over a period of 1 month; this was followed 1 month later by an antiviral combination with Peg-IFNa2b (1.5 mg/kg per week subcutaneously) plus ribavirin (600–1200 mg/day orally) for 12 months. For each patient, clinical and biological data were recorded at the time of the initial evaluation, at 3 months, 6 months,
9 months, 12 months and at the end of follow-up.
Results: Ten patients (62.5%) were complete clinical responders, five patients were partial responders, and one patient did not respond. Two patients with leg ulcers showed complete resolution, 11 out of 13 patients with purpura completely resolved, and 5 out of 6 patients with arthralgia completely resolved. Peripheral neuropathy completely responded in 5 out of 13 patients. Renal involvement improved in 7 out of 7 patients with all patients showing resolution of proteinuria and hematuria when present. A shorter duration of vasculitis and lower HCV viral load were predictors of complete response vs partial response.
Summary: Rituximab and antiviral therapy with interferon plus ribavirin seems to be very effective treatment for patients with mixed cryoglobulinemia associated with HCV. Further studies with long-term follow-up are warranted to ensure the long-term safety of this regimen.
Author’s Comments:
I have had personal experience with the use of rituximab in mixed cryoglobulinemia associated with auto-immune disease (SLE). This particular patient initially presented with chronic leg ulcers for over 5 years. She failed therapy with corticosteroids combined with azathioprine and cyclophosphamide. A worsening of her vasculitis resulted in therapy with plasma exchange combined with cyclophosphamide which was ineffective. Rituximab therapy (given as 375 mg/m2) was extremely effective resulting in complete resolution of the leg-ulcers. The patient recently received a second course of rituximab due to rising titers of RF, falling C4, and recurrence of small leg-ulcers.
Full Text of Article (adobe PDF) - Click HERE
ABSTRACT
D Saadoun, M Resche-Rigon, D Sene, L Perard, A Karras, and P Cacoub Rituximab combined with Peg-interferon-ribavirin in refractory hepatitis C virus-associated cryoglobulinaemia vasculitis
Ann Rheum Dis, Oct 2008; 67: 1431 - 1436.
D Saadoun 1, M Resche-Rigon 2, D Sene 1, L Perard 3, A Karras 4, P Cacoub 1
1 Pierre et Marie Curie-Paris 6 University I, CNRS UMR 7087, and Department of Internal Medicine, Hôpital Pitié-Salpétrière, Paris, France
2 Department of Biostatistics and Medical Data Processing, INSERM U717, Hôpital Saint-Louis, Paris, France
3 Department of Internal Medicine, Hôpital Edouard Herriot, Lyon, France
4 Department of Nephrology, Höpital European Georges Pompidou, Paris, France
Correspondence to:
Professor Patrice Cacoub, Université Pierre et Marie Curie-Paris 6, CNRS, UMR 7087, Paris, F-75013 France; AP-HP, Hôpital Pitié-Salpêtrière, Service de Médecine Interne, Paris, F-75013 France; patrice.cacoub@psl.aphp.fr
Objectives: To report the results of a pilot study using rituximab combined with Peg-interferon (IFN) 2b-ribavirin in severe refractory hepatitis C virus (HCV) related mixed cryoglobulinaemia (MC) vasculitis.
Methods: Sixteen consecutive patients with severe HCV-MC vasculitis that were resistant (n = 11) or relapser (n = 5) to a previous combination treatment with standard (n = 10) or Peg-IFN 2b (n = 6) plus ribavirin were included. They were treated with rituximab (375 mg/m2 intravenously weekly for 4 weeks) combined with Peg-IFN 2b (1.5 µg/kg per week subcutaneously) plus ribavirin (600–1200 mg/day orally) for 12 months.
Results: Fifteen patients (93.7%) showed clinical improvement, 10 of whom (62.5%) were clinical complete responders (CR). HCV RNA and serum cryoglobulin became undetectable in all the clinical CR. Peripheral blood B cell depletion was achieved in all patients (CD19+ cells, 111 (SD 32)/mm3 at baseline versus 2(2)/mm3 after the fourth infusion of rituximab) with reconstitution starting at the end of antiviral treatment. Compared with clinical CR, the partial or non-responders had a 3.6 times longer duration of vasculitis prior to treatment and a lower rate of early virological response. Treatment was well tolerated with no infectious complications. After a mean follow-up of 19.4 (SD 3.6) months, two patients experienced clinical relapse associated with a simultaneous reappearance of HCV RNA and cryoglobulin and an increase in the number of B cells.
Conclusions: Rituximab combined with Peg-IFN 2b-ribavirin represents a safe and effective treatment option in severe refractory HCV-MC vasculitis.
Reference List
(1) Ferri C, Greco F, Longombardo G et al. Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum. 1991;34:1606-1610.
(2) Lamprecht P, Lerin-Lozano C, Merz H et al. Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis. Ann Rheum Dis. 2003;62:1230-1233.
(3) Catuogno M, Rezai S, Priori R, Magrini L, Valesini G. Serum sickness associated with rituximab in a patient with hepatitis C virus-related mixed cryoglobulinaemia. Rheumatology (Oxford). 2005;44:406.
(4) Basse G, Ribes D, Kamar N et al. Rituximab therapy for mixed cryoglobulinemia in seven renal transplant patients. Transplant Proc. 2006;38:2308-2310.
(5) Cai FZ, Ahern M, Smith M. Treatment of cryoglobulinemia associated peripheral neuropathy with rituximab. J Rheumatol. 2006;33:1197-1198.
(6) Zaja F, Vianelli N, Sperotto A et al. Anti-CD20 therapy for chronic lymphocytic leukemia-associated autoimmune diseases. Leuk Lymphoma. 2003;44:1951-1955.
(7) Quartuccio L, Soardo G, Romano G et al. Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids. Rheumatology (Oxford). 2006;45:842-846.
(8) Roccatello D, Baldovino S, Rossi D et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant. 2004;19:3054-3061.
Edited by elisia - November 25 2008 at 3:08pm
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hudson
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| Posted: November 26 2008 at 7:56am
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I too have recently had a patient with cryoglobulinemic vasculitis in the context of chronic hepatitis C. She had frank arthritis, purpura, mononeuritis multiplex, high inflammatory parameters and hypocomplementemia. The hepatologist was taking his time doing something about the hepatitis so I started plasma exchange (around 6 treatments) with no improvement. The hepatologist was against the idea of cyclophosphamide. So I then gave her rituximab 1 gm IV x 2 (2 weeks apart). She had complete resolution of her symptoms, normalization of her complements and disappearance of her cryos. However, she has just been diagnosed with breast cancer! I guess rituxan is not helpful for that.
Marie Hudson
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dickson
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| Posted: December 25 2008 at 10:55pm
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Rituximab seems to have a lot of potential uses, particularly in difficult clinical situations where it is difficult to obtain. What concerns me is the sustained B cell resonse and the decision when to treat with other immunosuppresive agents in those who fail to respond to this therapy
John Dickson
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