Rheumatology Advance Access originally published online on May 5, 2006
Rheumatology 2006 45(6):784-785; doi:10.1093/rheumatology/kel135
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LETTER TO THE EDITOR |
Rituximab as possible first-line therapy for glomerulonephritis in HCV-related mixed cryoglobulinaemia
Rheumatology Clinic, DPMSC, University of Udine, Italy
Correspondence to: Salvatore De Vita, MD, Professor of Rheumatology, Chief, Rheumatology Clinic, DPMSC, University of Udine, Udine 33100, Italy.E-mail: salvatore.devita{at}med.uniud.it
SIR, Bruchfeld and colleagues either misunderstood or ignored the key message of our report [1], and reiterate their position statement on the role of anti-viral therapy in glomerulonephritis associated with hepatitis C virus (HCV) infection-related mixed cryoglobulinaemia (MC) syndrome [2], as already done with a previous Italian report in which less enthusiastic conclusions on this topic were reported [3]. The colleagues state that anti-viral therapy will and should remain the first-line therapy for HCV-related MC syndrome with nephritis.
In our opinion this systematic confrontational debate is not the best way to approach such a complex issue, and we hope to better compare and discuss the results and study approaches in future cooperative research.
The treatment of HCV-related MC syndrome with active nephritis is not easy, and should be tailored to the single patient giving the correct relevance to different clinical aspects. These may include age, comorbidity and concomitant MC manifestations, laboratory parameters, liver disease, efficacy and tolerability of previous therapies, and finally the putative risk/benefit ratio of the available treatment choices. Our patients [1] were treated with rituximab after a careful evaluation by expert clinicians from different departments (Rheumatology, Internal Medicine and Haematology), who chose rituximab instead of anti-viral therapy or other therapies for different reasons (thrombocytopenia and acute systemic symptoms in patient 1, anaemia, leucopenia, chronic renal failure and decompensated liver disease in patient 2, HCV genotype 1b and decompensated liver disease in patient 3, anaemia in patients 4 and 5). We were pleased of the efficacy and safety of rituximab therapy observed [1], and we wonder whether anti-viral therapy might have proved better. We and others [1, 4] did not observe the major side effects in MC nephritis when immunosuppressors and high-dose steroids were avoided with rituximab, and the steroid-sparing effect of rituximab in MC was stressed in our works [1, 5]. By contrast, the MC cases quoted by Bruchfeld developed serious infections under strong concomitant immunosuppressive therapy [6].
In our article, the efficacy and safety of rituximab in MC-related nephritis was highlighted. Thus, rituximab is now available also as a possible first treatment choice in the single patient, after a careful evaluation by the expert clinician. We believe that many nephritic patients with MC syndrome could benefit from this therapy if favourable preliminary experience is confirmed by larger controlled studies.
No controlled studies have ever been published on anti-viral therapy in MC-related nephritis. Nevertheless, Bruchfeld et al. [7] strongly suggested the use of pegylated interferon and ribavirin as first-line therapy in HCV-related MC syndrome with nephritis based on personal favourable results in 13 out of 16 HCV-positive cases (not all with MC syndrome). However, only five of them suffered from nephritis in MC syndrome [2, 7]. Despite favourable results in very small series or single MC nephritic cases reported by other authors, data are really very limited to allow clear-cut position statements in our opinion. Many experts currently use plasmapheresis, steroids and/or cyclophosphamide as a first-step therapy for MC nephritis, based on single situations [8].
Professor Cacoub was invited to join our controlled, randomized multicentre study on rituximab therapy compared with the ‘best available treatment’ in MC syndrome, which is currently ongoing, focusing on active nephritis, skin ulcers and peripheral neuropathy. Notably, one of the enrolment criteria is that patients must have previously failed anti-viral therapy, or this must be contra-indicated by an expert clinician.
Thus, our position is more balanced at present, and we gave no recommendation at all for rituximab as a first-line therapy for MC nephritis [1]. We are waiting for the results of the aforementioned controlled study for putative recommendations, if any, and we also used anti-viral therapy as a first-line approach in selected MC patients with nephritis in our clinic.
Antiviral therapy may be the optimal first-line strategy in HCV-related MC syndrome, always considering the possible difficulties in the short- and long-term managing, possible inefficacy, contraindications, severe adverse events and possible exacerbation or appearance of cryoglobulinaemic manifestations or MC syndrome itself [9, 10]. Moreover, concomitant steroids may be recommended [2], while they were minimized or avoided in our study [1].
Concerning the pathobiology issue, it should be emphasized that ongoing B-cell expansion may persist after HCV RNA serum disappearance in MC syndrome. Thus, other biological events besides viral infection may sustain the disease after its onset, and treatment strategies should focus on different possible targets, e.g. B cells themselves [1, 5].
Probably the unbiased expert clinician will be pleased today to consider a more expanded set of treatment options in the single nephritic patient [1, 4]. More caution in advocating or generalizing about the best first-line therapy should be used at present, in our opinion.
Rituximab might be compared to anti-viral therapy as a first-line approach in controlled studies. In addition, rituximab and anti-viral treatment combination, as well as sequential treatment approaches as induction and maintenance regimens, should also be explored. We aim to improve cooperative research to reach these objectives.
References
- Quartuccio L, Soardo G, Romano G et al. Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinemia: efficacy and safety in the absence of steroids. Rheumatology 2006 [Epub ahead of print published on January 17, 2006. doi.10.1093/rheumatology/kel004].
- Cacoub P, Saadoun D, Limal N, Sene D, Lidove O, Piette JC. PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2005;52:911–5[CrossRef][Medline]
- Mazzaro C, Zorat F, Caizzi M et al. Treatment with peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia: a pilot study. J Hepatol 2005;42:632–8.[CrossRef][Web of Science][Medline]
- Roccatello D, Baldovino S, Rossi D et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinemic glomerulonephritis. Nephrol Dial Transplant 2004;19:3054–61.
[Abstract/Free Full Text] - Zaja F, De Vita S, Mazzaro C et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003;101: 3827–34.
[Abstract/Free Full Text] - Basse G, Ribes D, Kamar N et al. Rituximab therapy for de novo mixed cryoglobulinemia in renal transplant patients. Transplantation 2005;80:1560–4.[CrossRef][Web of Science][Medline]
- Bruchfeld A, Lindahl K, Stahle L, Soderberg M, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003;18:1573–80.
[Abstract/Free Full Text] - Tavoni A, Mosca M, Ferri C et al. Guidelines for the management of essential mixed cryoglobulinemia. Clin Exp Rheumatol 1995;13:191–5.
- Levine JW, Gota C, Fessler BJ et al. Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol 2005;32:1164–7.
[Abstract/Free Full Text] - Beuthien W, Mellinghoff HU, Kempis J. Vasculitis complications of interferon-alpha treatment for chronic hepatitis C virus infection: case report and review of the literature. Clin Rheumatol 2005;24:507–15.[CrossRef][Web of Science][Medline]
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