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ARTICLES: C. Briani, L. Chemello, G. Zara, M. Ermani, E. Bernardinello, S. Ruggero, E. Toffanin, A. Gatta, L. Battistin, and L. Cavalletto Peripheral neurotoxicity of pegylated interferon alpha: A prospective study in patients with HCV Neurology 2006; 67: 781-785 [Abstract] [Full text] [PDF]

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Peripheral neurotoxicity of pegylated interferon alpha: A prospective study in patients with HCV

Franco Gemignani, Adriana Marbini   (4 December 2006)

Reply from the Authors

Chiara Briani   (4 December 2006)

Peripheral neurotoxicity of pegylated interferon alpha: A prospective study in patients with HCV 4 December 2006
Franco Gemignani, Department of Neurology, University of Parma Department of Neurology, University of Parma, 43100 Parma, Italy, Adriana Marbini Send Correspondence to journal: Re: Peripheral neurotoxicity of pegylated interferon alpha: A prospective study in patients with HCV franco.gemignani{at}unipr.it Franco Gemignani, et al.	We read with interest the article by Briani et al which showed that pegylated interferon alpha (PEG-IFNa) therapy was not associated with the occurrence or worsening of peripheral neuropathy or antibodies to peripheral nerve antigens in patients with hepatitis C virus (HCV). [1] This is important to dissipate major concerns about treating with PEG-IFNa patients with peripheral neuropathy. In this regard, the recent guidelines of the Italian Association of the Study of Liver (AISF) Commission on Extrahepatic Manifestations of HCV infection state that "IFN should be carefully administered to patients with severe sensorimotor neuropathy." [2] This is probably an overstatement considering that there is a rationale to treat with IFN such patients, as this therapy may eradicate HCV and cryoglobulinemia that are implicated in the pathogenesis of peripheral neuropathy, with benefit to the neuropathy itself. [3] Overall, these data favor a less cautious approach to IFN treatment of patients with neuropathy and HCV infection. However, some aspects remain to be explored as to neuropathy during IFN treatment, a likely idiosyncratic event demonstrated by occasional, but well documented, reports. [1] It is noteworthy that most reported HCV patients with IFN-induced or worsened neuropathy had cryoglobulinemia. In our series of patients with cryoglobulinemic neuropathy [4], a possible IFN-induced or worsened neuropathy was seen in 3 of 16 treated cases (unpublished data). Thus the focus should be shifted on the possible risk during IFN treatment for patients with HCV-related cryoglobulinemia to develop neuropathy and for patients with cryoglobulinemic neuropathy to worsen. The study of Briani et al [1] is not informative on this aspect, as they included only six patients with cryoglobulinemia (three with neuropathy) in the treated group. The conclusive step should be to investigate the occurrence or worsening of neuropathy during IFN treatment restricted to patients with cryoglobulinemia and the role of possible risk factors such as parameters of disease activity including cryocrit, complement levels, and rheumatoid factor. References 1. Briani C, Chemello L, Zara G, et al. Peripheral neurotoxicity of pegylated interferon alpha. A prospective study in patients with HCV. Neurology 2006;67:781-785. 2. Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB, for the Italian Association of the Study of Liver (AISF) Commission on Extrahepatic Manifestations of HCV infection. Extrahepatic manifestations of Hepatitis C Virus infection: A general overview and guidelines for a clinical approach. Dig Liver Dis 2006 (e-pub ahead of print) doi:10.1016/j.dld.2006.06.008 3. Khella SI, Frost S, Hermann GA, et al. Hepatitis C infection, cryoglobulinemia, and vasculitic neuropathy. Treatment with interferon alfa: case report and literature review. Neurology 1995;95:407-411. 4. Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry 2005;76:1410- 1414. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 4 December 2006
Chiara Briani, Dept. of Neurosciences, University of Padova Via Giustiniani, 5 - 35128 Padova, Italy Send Correspondence to journal: Re: Reply from the Authors chiara.briani{at}unipd.it Chiara Briani	We thank Drs. Gemignani and Marbini for their interest in our article on pegylated interferon alpha (PEG-IFNa) in HCV patients. [1] The aim of our study was to evaluate whether PEG-IFN therapy would be associated with worsening or occurrence of neuropathy or autoimmune response to peripheral nerve antigens in patients with chronic hepatitis C. The results did not show any correlation between IFN-alpha therapy and neuropathy in our HCV patients. We agree with Drs. Gemignani and Marbini that different mechanisms (individual susceptibility, action of the drug, heterogeneity of HCV population, cryoglobulins, vasculitis) may be implicated in IFN-alpha neurotoxicity as we stated in the discussion. Drs. Gemignani and Marbini call our attention to the possible role of cryoglobulinemia as a risk factor for IFN-alpha peripheral neurotoxicity. However, the patient population in our study cannot be used to address this issue. Of the 75 HCV patients considered, 11 had cryoglobulinemia, only 6 of whom were in the treated group. Recently, however, several studies evaluated IFN-alpha treatment in patients with HCV-related cryoglobulinemia. In a pilot study with PEG-IFN on 18 patients with HCV-associated mixed cryoglobulinemia, Mazzaro et al [5] reported improvement in 2 of 3 patients with neuropathy and did not observe occurrence of neuropathy in any other subject. In another study on 9 patients with HCV- cryoglobulinemia on a higher IFN-alpha dosage, Cacoub et al [6] reported a dramatic improvement in 3 of the 7 patients with polyneuropathy. Finally, the recent long-term study by Saadoun et al [7] adds further important information. Of 72 patients with HCV-associated cryoglobulinemia treated with IFN-alpha, 44 had neuropathy, 30 (68.2%) of whom showed complete improvement after therapy. None had a worsening of the neuropathy. Moreover, the presence of arthralgia and an early virological response was associated with a complete clinical response, whereas renal involvement, a glomerular filtration rate ¡Ü 70 mL/min, proteinuria, and corticosteroid use were negatively associated with response to IFN-alpha. In a multivariate analysis, an early virological response and the absence of renal insufficiency appeared to be crucial for the clinical response. These data provide clinicians with crucial information that might help select patients with HCV-related cryoglobulinemia that would be likely to respond to IFN-alpha. However, data on the possible factors associated with IFN-alpha neurotoxicity are lacking, since neurological manifestations did not develop or worsen in any patients. Until possible predictors of the neurological response to IFN-alpha therapy are identified, a close electrophysiological follow-up is recommended. References 5.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;42:632-638. 6.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;52:911-915. 7.Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P. Antiviral therapy for hepatitis C virus-associated mixed cryoglobulinemia vasculitis: A long-term followup study. Arthritis Rheum. 2006;5:3696-3706 [Epub ahead of print] Disclosure: The author reports no conflicts of interest.