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Cyclosporine A for the treatment of autoimmune disorders in HCV infected patients
Autoimmunity Reviews 5 (2006) 493 – 498 www.elsevier.com/locate/autrev
Cyclosporine A for the treatment of autoimmune disorders in HCV infected patients Mauro Galeazzi a,⁎, Francesca Bellisai a , Stefania Manganelli a , Gabriella Morozzi a , Gian Domenico Sebastiani b a
U.O.C. di Reumatologia, Policlinico Le Scotte-Viale Bracci 53100 Siena, Italy b U.O.C. di Reumatologia-A.O. San Camillo Forlanini-Roma, Italy Received 12 December 2005; accepted 17 January 2006 Available online 20 February 2006
Abstract Due to the relatively high prevalence of both HCV infection and autoimmune disorders (AD), it is not rare to encounter patients with AD also carrying HCV. Considering that the use in HCV infected individuals of corticosteroids or immunosuppressant drugs, that are indeed needed to treat AD, is considered a risk for worsening the clinical outcome of HCV infection, rheumatologist have often refrained from using these drugs in AD when HCV-RNA is also present. Cyclosporine (CsA) is an immunosuppressive agent used to treat a wide range of autoimmune disorders but there is in literature a large body of evidence suggesting that CsA also exerts an inhibitory effect on HCV replication at standard therapeutic dose. The anti-HCV effect of CsA has been demonstrated both in vitro and in vivo. Therefore, these evidences have opened new ways to improve the therapy and the prognosis in patients with HCV-related liver diseases including transplanted ones. Recent reports, although limited in number, also suggest the safety of CsA, in the treatment of patients with AD and concomitant HCV infection. Good results have also been obtained in the treatment in rheumatoid arthritis patients even in association with antiTNF agents. © 2006 Elsevier B.V. All rights reserved. Keywords: HCV infection; Cyclosporine A; Immunosuppressant; Autoimmune disorders; Anti-TNF
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CsA in the treatment of liver transplanted patients and in chronic active hepatitis In vitro evidences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CsA in autoimmune disorders with concomitant chronic HCV infection . . . . . Combined therapy of CsA and anti-TNFα agents in rheumatoid arthritis . . . . .
⁎ Corresponding author. Tel.: +39 0577 233345; fax: +39 0577 40450. E-mail address: [email protected] (M. Galeazzi). 1568-9972/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2006.01.002
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6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction It has been calculated that the prevalence of hepatitis C virus (HCV) infection is about 3% in western countries and that there are areas in south Italy where the prevalence rises up to 20% of the population. It is also known that, all together, autoimmune disorders (AD) have a prevalence of about 10% in western population, it is therefore not rare to encounter in daily clinical practice patients with AD also carrying HCV. The treatment of AD, especially in systemic severe forms, includes the usage of immunosuppressant agents and/or glucocorticoids that have the potential effect of worsening the outcome of HCV infection. For this reason rheumatologist have often refrained from using immunosuppressants in AD when HCV-RNA is also present. Cyclosporine A (CsA) is an immunosuppressive agent used to treat a wide range of autoimmune disorders but there are sufficient evidences suggesting that CsA also exerts antiviral effects being able to inhibit HCV viral replication in vitro. This ability has also been confirmed in vivo, in liver transplanted patients and in patients affected by chronic active hepatitis (CAH). Nevertheless, very little is known about the efficacy and safety of CsA in patients with autoimmune disorders and concomitant chronic HCV infection. For the present paper, we have reviewed the current literature focusing our attention on the in vitro and in vivo evidences of anti-HCV action of CsA and on the antiviral mechanism of action of CsA. We have also reported personal and others experiences with CsA in the treatment of autoimmune disorders in the presence of chronic HCV infection. 2. CsA in the treatment of liver transplanted patients and in chronic active hepatitis Cirrhosis caused by chronic hepatitis is responsible for approximately one-half of all liver transplantation procedures [1]. Recurrence of HCV infection occurs in up to 90% of cases following liver transplantation [2]. The increased viral replication, the frequent development of histological features characteristic of chronic hepatitis and the increased incidence of HCV-related disease progression in transplant patients was attributed to the effect of immunosuppressive therapy [3–5].
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Nevertheless, some clinical trials, in HCV+ liver transplanted patients [6], have suggested that the outcome could be improved when CsA is included in the therapeutic regimen. The effectiveness of CsA in de novo liver transplant patients was investigated in the LIS2T trial [6]. This was the first multicenter, open-label, randomised study comparing the efficacy and safety of CsA microemulsion (ME) versus tacrolimus. The study randomised 495 patients to receive either CsA-ME (n = 250) or TAC (n = 245), in combination with steroids, with/without azathioprine, for 6 months. No differences were found in the two groups about the incidence of biopsy-proven acute rejection at 3 months and at 6 months but death or graft loss was more frequent in those receiving tacrolimus (15% vs. 6%, P < 0.05). A further analysis performed on 129 patients from one center showed that at 3 years post-transplantation, in HCV+ patients CsA treatment resulted in better survival (90% vs. 78%; p < 0.05), lower viral titres (1.05 vs. 3.2; p < 0.05) and markedly improved hepatic biochemical tests [6]. These results demonstrated that CsA treatment results in decreased frequency of both death and graft loss in HCV+ patients. Casanovas Taltavull also studied 14 HCV+ liver transplant patients treated with IFN-α + ribavirin and immunosuppressed with CsA or TAC monotherapy. The results showed that a sustained virological response was achieved in 6 patients while the others were nonresponders. Interestingly, all the responders were receiving CsA treatment, while 6 out of 8 nonresponders were on TAC therapy [7]. In another study, Kugelmas et al. [8] showed that liver transplanted patients treated with CsA have earlier HCV clearance (from 12 weeks to 7 months) in comparison to those treated with TAC (from 3 to 18 months). Ghobrial et al. [9] have also shown that CsA treatment was associated with a longer time interval to re-transplantation in liver transplant patients with recurrence of hepatitis C disease (mean interval: 787 ± 805 days for CsA patients and 142 ± 34 days for TAC; p = 0.09). Histological progression of chronic HCV-associated hepatitis to fibrosis is a critical step in disease progression that often leads to cirrhosis and decompensation. Berenguer et al. evaluated the histological
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progression of hepatitis to fibrosis [10]. A total of 1353 biopsies were performed on 554 HCV+ patients that had undergone transplantation at least 1 year before. Therapeutic regimens without CsA was significantly associated with development of advanced liver fibrosis (stages 3–4) in fact 29% of those who did not receive CsA developed severe fibrosis, while only 14% of patients treated with CsA progressed to advanced stages of fibrosis (p < 0.05). A similar study was performed by Duvoux et al. in which 96 transplant patients were followed for HCV-related cirrhosis [11]. Univariate analysis showed that the rate of progression of fibrosis was significantly lower in patients receiving CsA and multivariate analysis showed that tacrolimus was an independent risk factor for fibrosis progression. Recently, Nakamuta et al. [12] have investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production in hepatic stellate cells (HSC) that are considered to be central to hepatic fibrosis. In their study, the authors demonstrated that cyclosporine suppresses cell growth and collagen production and suggested that cyclosporine might also exert an antifibrogenesis effect. The need of using therapeutic protocols in HCV+ transplant patients that prevent organ graft rejection in addition to viral replication has highlighted the potential pivotal role of CsA. There is in fact some evidence suggesting that switching from tacrolimus to CsA could result in an improvement in the viral and biological response without negative impact on the graft in HCV+ liver transplant patients. The aforementioned preclinical and clinical data, suggest that switching from other immunosuppressive regimens to CsA could be considered for transplanted patients with a history of HCV viral infection. since a lower rejection risk should correlate with fewer doses of corticoids, a known negative prognostic factor. Furthermore, Inoue et al. [13] conducted a controlled study in order to assess the efficacy, safety and tolerability of combination therapy with IFN-α and CsA, which demonstrated that these two agents in combination are more effective than the drugs given alone and have a favourable safety profile. These results suggest that CsA has the potential to play a key therapeutic role in transplant patients too, providing enough immunosuppression to avoid graft rejection and disfavour viral replication without reducing the overall immunosuppressive load [14]. In fact, the persistence of T-cell reactivity also during immunosuppressive therapies is important for the control of HCV replication that should be pursued without completely abrogating the
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activity of the immune system. The synergistic effect of CsA with antiviral drugs, together with the optimisation of dosage by C2 monitoring, may allow such a possibility. 3. In vitro evidences These observations prompted to evaluate in vitro CsA antiviral activity utilizing an HCV sub-genomic replicon transfected in Huh-7 cells (HCV replicon cells). This represents a unique tool to study mechanisms controlling viral replication and to screen the activity of potential anti-HCV compounds [15]. HCV replicon cells have been used to evaluate the effect on HCV replication of CsA and several immunosuppressants [16]. Treatment with CsA or IFN-α resulted in a decrease in the HCV proteins NS5A and NS5B to undetectable levels by Western blot analysis demonstrating the absence of viral proteins in treated cells. Reduction of viral proteins was not observed upon treatment with other immunosuppressants such as tacrolimus (TAC). Moreover, treatment with both CsA and IFN-α decreased the amount of replicon RNA to undetectable levels by Northern blot analysis, while TAC was ineffective. When RNA levels were quantified by real-time RT-PCR (reverse transcriptase polymerase chain reaction), CsA caused dose-dependent decreases in the levels of replicon RNA to about 1/500 of the original value, while IFN-α treatment lowered the titre to around 1/400. In addition, simultaneous treatment with CsA and IFN-α further reduced RNA levels to about 1/5 of those observed with IFN-α alone. It should be underlined that the ability of CsA to reduce the levels of both HCV-RNA and proteins was highly specific; this activity was not attributable to interference with cell growth, indicating that impaired replication of HCV is not due to cytotoxic effects. To demonstrate that CsA is also effective in inhibiting HCV replication in a hepatic setting, Watashi et al. treated human hepatocytes with HCV+ plasma [16]. When evaluated by real-time RT-PCR, the viral titre rapidly augmented in control cells, while no significant increases were observed in cells treated with either CsA or IFN-α. These results are highly suggestive that CsA is also effective in inhibiting HCV replication in infected hepatocytes as well. 4. CsA in autoimmune disorders with concomitant chronic HCV infection It is well known that chronic HCV infection may be responsible for the appearance several autoimmune or
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immune-mediated conditions [17,18]. On the other hand, it is not rare to encounter patients affected by autoimmune disorders who also carry HCV. These clinical situations are very similar to those found in liver transplanted patients, in fact in both conditions is mandatory to give patients corticosteroids and/or immune-suppressants to treat the autoimmune disorders but it is often necessary to give also with antiviral agents to treat the viral infection. Nevertheless, the risk of worsening HCV infection outcome by giving a strong immune-suppression, has refrained rheumatologist from using these therapies with the risk, in turn, of not treating properly the autoimmune disorder. The recent discovery of the anti-HCV effect of CsA has opened new perspectives for a more safe and effective treatment in these conditions. Nevertheless, as far as we know, only one case report can be found in literature, by Miura et al. [19], who described four patients affected by dermatological disorders and HCV infection treated with CsA with a wing dose of 3 mg/kg daily. These patients were affected, respectively, by nummular dermatitis and autosensitization dermatitis, by psoriasis vulgaris, by psoriasis pustulosa and by prurigo nodularis; they have used a starting dose of CsA of 3 mg/kg daily. In their experience, the authors showed that long-term administration of CsA (from 24 to 36 months) was safe and reduced HCV load and aminotransferase levels in three out of four patients. In order to evaluate the safety and the antiviral effect of CsA in patients with ADs and concomitant HCV infection, we have conducted a pilot study in 7 individuals [20,21]. Three patients were males and four females, mean age was 56.8 ± 8.8 years and mean disease duration (time of diagnosis) was 11 ± 7.5 years. Our patients were affected, respectively, by HCV related symptomatic mixed cryoglobulinemia in 4 cases, Sjogren syndrome in 1 case and rheumatoid arthritis in 3 cases; two patients also had CAH. HCV genotypes were 2c (2 cases), 1b (2 cases), 1a (1 case), 2a (1 case) and 3a/3c (1 case). Patients were treated, for a period of time ranging from 6 to 12 months, with 3mg/kg of CsA and glucocorticoids at the mean dose of 17.5mg of prednisone. Liver function tests were controlled every month and serum HCV-RNA load was controlled by RT-PCR before treatment and then every 2 months during therapy. After 6 months aminotransferase levels significantly decreased in two patients with CAH (p = 0.05) and no modifications were seen in the others who had normal levels before treatment. Hepatitis C virus-RNA load significantly decreased in four patients who showed higher levels before treatment (p = 0.004). No modifications of viral load were seen in patients who
had low RNA levels before treatment. Notably, after 8 months of CsA therapy, in one patient with RA, and concomitant 1b viral genotype infection with CAH, the HCV-RNA test resulted negative and was still negative after 2 months and serum aminotransferases slowly returned to normal limits and remained normal over time. Mean prednisone dose was significantly reduced after 6 months of therapy from the initial 17.5 mg/day to 12.5mg/day. Our results allowed us to draw some conclusions. First of all we can confirm the safety of CsA in the treatment of AD with concomitant HCV infection even in patients with CAH. Moreover, we found evidences suggesting that CsA can be safe in the presence of all HCV genotypes even in patients with high viral load. There are also evidences that CsA can reduce HCVRNA load even in patients with AD. 5. Combined therapy of CsA and anti-TNFα agents in rheumatoid arthritis Tumour necrosis factor α (TNFα) is a key cytokine in the integrated host defence system against infectious diseases. While clinical trials of anti-TNFα agents, in a number of AD, generally did not note increased susceptibility to typical or opportunistic infections, post-marketing analysis has clearly demonstrated an increased susceptibility to infections especially those caused by Mycobacterium tuberculosis, atypical mycobacteria as well as other intra-cellular organisms [22,23]. Considering also that TNFα blockers have to be given in combination with methotrexate, or other immunosuppressant agents, rheumatologist are refrained to use anti-TNFα in patients with AD and concomitant chronic HCV infection. On the other hand there are studies, dedicated to identify predictors of response to therapy in patients with HCV infection, that have suggested a central role for host factors in the outcome of therapy [24,25]. In particular, TNFα has been implicated in refractoriness to IFN therapy in HCV patients. The subject of the role of TNFα, and of the imbalance of h1/h2 T lymphocytes response, in the development of HCV chronic infection and in determining the refractoriness to antiviral therapies, has been recently reviewed by Calabrese et al. [26]. In acute selflimited HCV infection, circulating Th cells have been shown to predominantly produce IFNγ, suggesting a Th 1-like response [27]. Similarly, while patients who are able to spontaneously clear acute HCV infections have a strong Th 1 response without detectable Th 2 response, those who become chronically infected have a dominant Th 2 response [28]. Furthermore, very preliminary data
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are available on the use of existing anti-TNF agents in patients with chronic HCV infection that show the safety of these agents in this condition [29]. Concerning the treatment of patients with concomitant AD, a study of 24 patients with chronic HCV infection and rheumatoid arthritis, who received anti-TNF therapy (etanercept or infliximab), has been recently reported [30]. No significant adverse events were seen in these patients. No statistically significant changes were noted in the liver aminotransferases or in HCV-RNA viral loads yet 16/22 patients with pre-treatment and post-treatment HCV-RNA measurements showed decline in viral load [30]. A retrospective multicenter study, focused on the treatment of HCV-RNA positive RA subjects with antiTNFα agents, is ongoing in Italy (GISEA study group). Our personal contribution to this study is made of 6 patients and we can confirm the safety of the therapy in HCV infected patients with RA. Interestingly, in two of this patients anti-TNF were added to CsA because of its clinical and biological inefficacy. In one case, Adalimumab (Humira) was given at the standard dose of 40 mg every 2 weeks subcutaneously (s.c.), in the second Etanercept (Enbrel) was administrated s.c. at the dosage of 25 mg twice a week. These patients have been treated for 6 months and no detectable side effects were seen so far. Aminotransferases remained within normal limits and viral load did not increase. As far as we know this is the first report describing the safety of CsA and anti-TNF combined therapy in HCV positive RA patients. 6. Conclusions Autoimmune disorders and HCV chronic infection can frequently occur in the same patient. In this case, the treatment of AD may become difficult due to the well-known risk to worsen the HCV infection outcome with the use of corticosteroids and/or immunosuppressants. In fact, the experiences accumulated in transplanted patients clearly show that while a potent immunosuppressive regimen prevents allograft rejection, it also favours viral replication and facilitates viral-mediated graft injury. Recent in vitro studies together with clinical data have demonstrated that CsA has substantial antiviral activity. CsA can thus act as a dual-action drug by decreasing the activity of the immune system, thus avoiding graft rejection in transplanted patients and virus replication also in AD patients, and by interfering with viral replication that can lead in both cases, to the damage of the organ. Information in literature, concerning safety and efficacy
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of CsA in the treatment of HCV+ AD patients, is limited to few case reports, nevertheless evidence have been found that CsA can be safely used also in these conditions. Therefore, we can conclude that even if further prospective trials are required to confirm the efficacy and safety of CsA in HCV+ individuals, the available data are highly suggestive that the use of CsA contributes to better outcome also in patients affected by AD and concomitant HCV infection with or without CAH. Take-home messages •
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In vitro and in vivo studies, in liver transplanted patients and in patients with CAH, demonstrate that CsA exert an inhibitory effect on HCV replication. Preliminary studies suggest that CsA can be safely used in the treatment of patients affected by autoimmune disorders with concomitant chronic HCV infection.
References [1] Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001;35:666–78. [2] Wright TL, Donegan E, Hsu HH, Ferrell L, Lake JR, Kim M, et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterology 1992;103:317–22. [3] Chazouilleres O, Kim M, Combs C, Ferrell L, Bacchetti P, Roberts J, et al. Quantitation of hepatitis C virus RNA in liver transplant recipients. Gastroenterology 1994;106:994–9. [4] Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol Apr 2000;32 (4):673–84. [5] McCaughan GW. Immunosuppression for HCV following liver transplantation: enough is just enough. Transplantation 2004;78:1413–4. [6] Levy G, Villamil F, Samuel D, Sanjuan F, Grazi GL, Wu Y, et al. Results of LIS2T, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation. Transplantation 2004;77:1632–8. [7] Casanovas Taltavull T. Impact of cyclosporine on the development of immunosuppressive therapy in liver transplantation. Transplant Proc 2004;36:S291–4. [8] Kugelmas M, Osgood MJ, Trotter JF, Bak T, Wachs M, Forman L, et al. Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection. Liver Transpl 2003;9: 1159–65. [9] Ghobrial RM, Farmer DG, Baquerizo A, Colquhoun S, Rosen HR, Yersiz H, et al. Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center cells. Transplant Proc Dec 2005;37(10):4598–602. [10] Berenguer M, Crippin J, Gish R, Bass N, Bostrom A, Netto G, et al. A model to predict severe HCV-related disease following liver transplantation. Hepatology 2003;38:34–41.
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[11] Duvoux C, Mennecier D, Pageaux G. Immunosuppression with tacrolimus and absence of antihypertensive therapy are associated with fibrosis progression after hepatitis C virus graft reinfection. International society of transplantation congress; 2002. abs. 2652. [12] Nakamuta M, Kohjima M, Fukushima M, Morizono S, Kotoh K, Kobayashi N, et al. Cyclosporine suppresses cell growth and collagen production in hepatic stellate cells. Transplant Proc Dec 2005;37(10):4598–602. [13] Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol 2003;38:567–72. [14] Everson GT. Impact of immunosuppressive therapy on recurrence of hepatitis C. Liver Transpl 2002;8:19–27. [15] Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science Jul 2 1999;285 (5424):110–3. [16] Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003;38(5):1282–8. [17] Sebastiani GD, Bellisai F, Caudai C, Rottoli P, Valensin PE, Pippi L, et al. Association of extrahepatic manifestations with HLA class II alleles and with virus genotype in HCV infected patients. J Biol Regul Homeost Agents Jan–Jun 2005;19(1–2):17–22. [18] Galeazzi M, Manganelli S, Bellisai F, Gonnelli L. HCV e malattie autoimmuni. Riv It Biol Med 1996;16:91–101. [19] Miura H, Itoh Y, Matsumoto Y, Tani M, Tanabe N, Isonokami M, et al. Long-term administration of cyclosporin A to HCVantibody-positive patients with dermatologic diseases. Int J Dermatol Apr 1999;38(4):310–4. [20] Galeazzi M, Bellisai F, Sebastiani GD, Giannitti C, Garcia Gonzales E. Utilizzo della ciclosporina in pazienti HCV positivi. Reumatismo 2005;57(4):122–4 [numero speciale 3].
[21] Donvito A, Bellisai F, Morozzi G, Crisanti A, Galeazzi M. La ciclosporina A nel trattamento dei disordini autoimmuni in pazienti con infezione cronica da HCV: studio pilota in aperto. Reumatismo 2005;57(4):265 [(numero speciale 3) abstract C03]. [22] Safety update on TNF-α antagonists: infliximab and etanercept. Food and Drug Administration, Arthritis Drugs Advisory Committee, 17 August 2001. Available at: www.fda/gov/ ohrms/dockets/ac/01/transcripts/3779+2_01.pdf [accessed 29 July 2004]. [23] Ellerin T, Rubin RH, Weinblatt ME. Infections and anti-tumor necrosis factor alpha therapy. Arthritis Rheum 2003;48:3013–22. [24] Di Bisceglie AM, Hoofnagle JH. Optimal therapy of hepatitis C. Hepatology 2002;36:S121–7. [25] Lindsay KL. Introduction to therapy of hepatitis C. Hepatology 2002;36:S114–20. [26] Calabrese LH, Zein N, Vassilopoulos D. Safety of anti-tumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection. Ann Rheum Dis Nov 2004;63(Suppl 2):ii18–24. [27] Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC, et al. Possible mechanism involving Tlymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 1995;346:1006–7. [28] Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC. Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity. Hepatology 1997; 25:449–58. [29] Zein NN. A phase II randomised, double blind, placebo controlled study of tumor necrosis factor antagonist (Etanercept, Enbrel) as an adjuvant to interferon and ribavirin in naive patients with chronic hepatitis C [abstract]. Hepatology 2002;36:504A. [30] Peterson JR, Hsu FC, Simkin PA, Wener MH. Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003;62:1078–82.
Autoimmune disease in asthma Previous research has suggested an inverse relationship between Th2-related atopic disorders, such as asthma, and Th1-related autoimmune diseases. In this study, Tirosh A, et al. (Ann Intern Med 2006; 144: 877-83) assessed the rate of newly diagnosed autoimmune disorders in a large cohort of young adults. Using cross-sectional data from the Israeli Defense Force database, the prevalence of autoimmune disorders was analyzed in asthmatic and nonasthmatic 307 367 male and 181 474 female military personnel between 1980 and 2003. Cases of type 1 diabetes mellitus, vasculitis, immune thrombocytopenic purpura, inflammatory bowel disease, rheumatoid arthritis, and the antiphospholipid syndrome were studied. Of 488 841 participants at enrollment, significantly more women than men had autoimmune disorders. Compared with asthmatic women, nonasthmatic women had a significantly higher prevalence of autoimmune disorders except for the antiphospholipid syndrome. During the follow-up period, vasculitis and rheumatoid arthritis were more frequently diagnosed in nonasthmatic persons of both sexes. There was a significant higher incidence of immune thrombocytopenic purpura, inflammatory bowel disease, and the antiphospholipid syndrome in nonasthmatic women and a statistically significantly higher incidence of type I diabetes mellitus in nonasthmatic men. Thus, asthma status may affect the prevalence of major autoimmune disorders. Preexisting asthma seems to protect against the development of autoimmune disorders to varying degrees in men and women.
Cyclosporine A for the treatment of autoimmune disorders in HCV infected patients Mauro Galeazzi a,⁎, Francesca Bellisai a , Stefania Manganelli a , Gabriella Morozzi a , Gian Domenico Sebastiani b a
U.O.C. di Reumatologia, Policlinico Le Scotte-Viale Bracci 53100 Siena, Italy b U.O.C. di Reumatologia-A.O. San Camillo Forlanini-Roma, Italy Received 12 December 2005; accepted 17 January 2006 Available online 20 February 2006
Abstract Due to the relatively high prevalence of both HCV infection and autoimmune disorders (AD), it is not rare to encounter patients with AD also carrying HCV. Considering that the use in HCV infected individuals of corticosteroids or immunosuppressant drugs, that are indeed needed to treat AD, is considered a risk for worsening the clinical outcome of HCV infection, rheumatologist have often refrained from using these drugs in AD when HCV-RNA is also present. Cyclosporine (CsA) is an immunosuppressive agent used to treat a wide range of autoimmune disorders but there is in literature a large body of evidence suggesting that CsA also exerts an inhibitory effect on HCV replication at standard therapeutic dose. The anti-HCV effect of CsA has been demonstrated both in vitro and in vivo. Therefore, these evidences have opened new ways to improve the therapy and the prognosis in patients with HCV-related liver diseases including transplanted ones. Recent reports, although limited in number, also suggest the safety of CsA, in the treatment of patients with AD and concomitant HCV infection. Good results have also been obtained in the treatment in rheumatoid arthritis patients even in association with antiTNF agents. © 2006 Elsevier B.V. All rights reserved. Keywords: HCV infection; Cyclosporine A; Immunosuppressant; Autoimmune disorders; Anti-TNF
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CsA in the treatment of liver transplanted patients and in chronic active hepatitis In vitro evidences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CsA in autoimmune disorders with concomitant chronic HCV infection . . . . . Combined therapy of CsA and anti-TNFα agents in rheumatoid arthritis . . . . .
⁎ Corresponding author. Tel.: +39 0577 233345; fax: +39 0577 40450. E-mail address: [email protected] (M. Galeazzi). 1568-9972/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2006.01.002
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6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction It has been calculated that the prevalence of hepatitis C virus (HCV) infection is about 3% in western countries and that there are areas in south Italy where the prevalence rises up to 20% of the population. It is also known that, all together, autoimmune disorders (AD) have a prevalence of about 10% in western population, it is therefore not rare to encounter in daily clinical practice patients with AD also carrying HCV. The treatment of AD, especially in systemic severe forms, includes the usage of immunosuppressant agents and/or glucocorticoids that have the potential effect of worsening the outcome of HCV infection. For this reason rheumatologist have often refrained from using immunosuppressants in AD when HCV-RNA is also present. Cyclosporine A (CsA) is an immunosuppressive agent used to treat a wide range of autoimmune disorders but there are sufficient evidences suggesting that CsA also exerts antiviral effects being able to inhibit HCV viral replication in vitro. This ability has also been confirmed in vivo, in liver transplanted patients and in patients affected by chronic active hepatitis (CAH). Nevertheless, very little is known about the efficacy and safety of CsA in patients with autoimmune disorders and concomitant chronic HCV infection. For the present paper, we have reviewed the current literature focusing our attention on the in vitro and in vivo evidences of anti-HCV action of CsA and on the antiviral mechanism of action of CsA. We have also reported personal and others experiences with CsA in the treatment of autoimmune disorders in the presence of chronic HCV infection. 2. CsA in the treatment of liver transplanted patients and in chronic active hepatitis Cirrhosis caused by chronic hepatitis is responsible for approximately one-half of all liver transplantation procedures [1]. Recurrence of HCV infection occurs in up to 90% of cases following liver transplantation [2]. The increased viral replication, the frequent development of histological features characteristic of chronic hepatitis and the increased incidence of HCV-related disease progression in transplant patients was attributed to the effect of immunosuppressive therapy [3–5].
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Nevertheless, some clinical trials, in HCV+ liver transplanted patients [6], have suggested that the outcome could be improved when CsA is included in the therapeutic regimen. The effectiveness of CsA in de novo liver transplant patients was investigated in the LIS2T trial [6]. This was the first multicenter, open-label, randomised study comparing the efficacy and safety of CsA microemulsion (ME) versus tacrolimus. The study randomised 495 patients to receive either CsA-ME (n = 250) or TAC (n = 245), in combination with steroids, with/without azathioprine, for 6 months. No differences were found in the two groups about the incidence of biopsy-proven acute rejection at 3 months and at 6 months but death or graft loss was more frequent in those receiving tacrolimus (15% vs. 6%, P < 0.05). A further analysis performed on 129 patients from one center showed that at 3 years post-transplantation, in HCV+ patients CsA treatment resulted in better survival (90% vs. 78%; p < 0.05), lower viral titres (1.05 vs. 3.2; p < 0.05) and markedly improved hepatic biochemical tests [6]. These results demonstrated that CsA treatment results in decreased frequency of both death and graft loss in HCV+ patients. Casanovas Taltavull also studied 14 HCV+ liver transplant patients treated with IFN-α + ribavirin and immunosuppressed with CsA or TAC monotherapy. The results showed that a sustained virological response was achieved in 6 patients while the others were nonresponders. Interestingly, all the responders were receiving CsA treatment, while 6 out of 8 nonresponders were on TAC therapy [7]. In another study, Kugelmas et al. [8] showed that liver transplanted patients treated with CsA have earlier HCV clearance (from 12 weeks to 7 months) in comparison to those treated with TAC (from 3 to 18 months). Ghobrial et al. [9] have also shown that CsA treatment was associated with a longer time interval to re-transplantation in liver transplant patients with recurrence of hepatitis C disease (mean interval: 787 ± 805 days for CsA patients and 142 ± 34 days for TAC; p = 0.09). Histological progression of chronic HCV-associated hepatitis to fibrosis is a critical step in disease progression that often leads to cirrhosis and decompensation. Berenguer et al. evaluated the histological
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progression of hepatitis to fibrosis [10]. A total of 1353 biopsies were performed on 554 HCV+ patients that had undergone transplantation at least 1 year before. Therapeutic regimens without CsA was significantly associated with development of advanced liver fibrosis (stages 3–4) in fact 29% of those who did not receive CsA developed severe fibrosis, while only 14% of patients treated with CsA progressed to advanced stages of fibrosis (p < 0.05). A similar study was performed by Duvoux et al. in which 96 transplant patients were followed for HCV-related cirrhosis [11]. Univariate analysis showed that the rate of progression of fibrosis was significantly lower in patients receiving CsA and multivariate analysis showed that tacrolimus was an independent risk factor for fibrosis progression. Recently, Nakamuta et al. [12] have investigated the effects of cyclosporine or tacrolimus on cell growth and collagen production in hepatic stellate cells (HSC) that are considered to be central to hepatic fibrosis. In their study, the authors demonstrated that cyclosporine suppresses cell growth and collagen production and suggested that cyclosporine might also exert an antifibrogenesis effect. The need of using therapeutic protocols in HCV+ transplant patients that prevent organ graft rejection in addition to viral replication has highlighted the potential pivotal role of CsA. There is in fact some evidence suggesting that switching from tacrolimus to CsA could result in an improvement in the viral and biological response without negative impact on the graft in HCV+ liver transplant patients. The aforementioned preclinical and clinical data, suggest that switching from other immunosuppressive regimens to CsA could be considered for transplanted patients with a history of HCV viral infection. since a lower rejection risk should correlate with fewer doses of corticoids, a known negative prognostic factor. Furthermore, Inoue et al. [13] conducted a controlled study in order to assess the efficacy, safety and tolerability of combination therapy with IFN-α and CsA, which demonstrated that these two agents in combination are more effective than the drugs given alone and have a favourable safety profile. These results suggest that CsA has the potential to play a key therapeutic role in transplant patients too, providing enough immunosuppression to avoid graft rejection and disfavour viral replication without reducing the overall immunosuppressive load [14]. In fact, the persistence of T-cell reactivity also during immunosuppressive therapies is important for the control of HCV replication that should be pursued without completely abrogating the
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activity of the immune system. The synergistic effect of CsA with antiviral drugs, together with the optimisation of dosage by C2 monitoring, may allow such a possibility. 3. In vitro evidences These observations prompted to evaluate in vitro CsA antiviral activity utilizing an HCV sub-genomic replicon transfected in Huh-7 cells (HCV replicon cells). This represents a unique tool to study mechanisms controlling viral replication and to screen the activity of potential anti-HCV compounds [15]. HCV replicon cells have been used to evaluate the effect on HCV replication of CsA and several immunosuppressants [16]. Treatment with CsA or IFN-α resulted in a decrease in the HCV proteins NS5A and NS5B to undetectable levels by Western blot analysis demonstrating the absence of viral proteins in treated cells. Reduction of viral proteins was not observed upon treatment with other immunosuppressants such as tacrolimus (TAC). Moreover, treatment with both CsA and IFN-α decreased the amount of replicon RNA to undetectable levels by Northern blot analysis, while TAC was ineffective. When RNA levels were quantified by real-time RT-PCR (reverse transcriptase polymerase chain reaction), CsA caused dose-dependent decreases in the levels of replicon RNA to about 1/500 of the original value, while IFN-α treatment lowered the titre to around 1/400. In addition, simultaneous treatment with CsA and IFN-α further reduced RNA levels to about 1/5 of those observed with IFN-α alone. It should be underlined that the ability of CsA to reduce the levels of both HCV-RNA and proteins was highly specific; this activity was not attributable to interference with cell growth, indicating that impaired replication of HCV is not due to cytotoxic effects. To demonstrate that CsA is also effective in inhibiting HCV replication in a hepatic setting, Watashi et al. treated human hepatocytes with HCV+ plasma [16]. When evaluated by real-time RT-PCR, the viral titre rapidly augmented in control cells, while no significant increases were observed in cells treated with either CsA or IFN-α. These results are highly suggestive that CsA is also effective in inhibiting HCV replication in infected hepatocytes as well. 4. CsA in autoimmune disorders with concomitant chronic HCV infection It is well known that chronic HCV infection may be responsible for the appearance several autoimmune or
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immune-mediated conditions [17,18]. On the other hand, it is not rare to encounter patients affected by autoimmune disorders who also carry HCV. These clinical situations are very similar to those found in liver transplanted patients, in fact in both conditions is mandatory to give patients corticosteroids and/or immune-suppressants to treat the autoimmune disorders but it is often necessary to give also with antiviral agents to treat the viral infection. Nevertheless, the risk of worsening HCV infection outcome by giving a strong immune-suppression, has refrained rheumatologist from using these therapies with the risk, in turn, of not treating properly the autoimmune disorder. The recent discovery of the anti-HCV effect of CsA has opened new perspectives for a more safe and effective treatment in these conditions. Nevertheless, as far as we know, only one case report can be found in literature, by Miura et al. [19], who described four patients affected by dermatological disorders and HCV infection treated with CsA with a wing dose of 3 mg/kg daily. These patients were affected, respectively, by nummular dermatitis and autosensitization dermatitis, by psoriasis vulgaris, by psoriasis pustulosa and by prurigo nodularis; they have used a starting dose of CsA of 3 mg/kg daily. In their experience, the authors showed that long-term administration of CsA (from 24 to 36 months) was safe and reduced HCV load and aminotransferase levels in three out of four patients. In order to evaluate the safety and the antiviral effect of CsA in patients with ADs and concomitant HCV infection, we have conducted a pilot study in 7 individuals [20,21]. Three patients were males and four females, mean age was 56.8 ± 8.8 years and mean disease duration (time of diagnosis) was 11 ± 7.5 years. Our patients were affected, respectively, by HCV related symptomatic mixed cryoglobulinemia in 4 cases, Sjogren syndrome in 1 case and rheumatoid arthritis in 3 cases; two patients also had CAH. HCV genotypes were 2c (2 cases), 1b (2 cases), 1a (1 case), 2a (1 case) and 3a/3c (1 case). Patients were treated, for a period of time ranging from 6 to 12 months, with 3mg/kg of CsA and glucocorticoids at the mean dose of 17.5mg of prednisone. Liver function tests were controlled every month and serum HCV-RNA load was controlled by RT-PCR before treatment and then every 2 months during therapy. After 6 months aminotransferase levels significantly decreased in two patients with CAH (p = 0.05) and no modifications were seen in the others who had normal levels before treatment. Hepatitis C virus-RNA load significantly decreased in four patients who showed higher levels before treatment (p = 0.004). No modifications of viral load were seen in patients who
had low RNA levels before treatment. Notably, after 8 months of CsA therapy, in one patient with RA, and concomitant 1b viral genotype infection with CAH, the HCV-RNA test resulted negative and was still negative after 2 months and serum aminotransferases slowly returned to normal limits and remained normal over time. Mean prednisone dose was significantly reduced after 6 months of therapy from the initial 17.5 mg/day to 12.5mg/day. Our results allowed us to draw some conclusions. First of all we can confirm the safety of CsA in the treatment of AD with concomitant HCV infection even in patients with CAH. Moreover, we found evidences suggesting that CsA can be safe in the presence of all HCV genotypes even in patients with high viral load. There are also evidences that CsA can reduce HCVRNA load even in patients with AD. 5. Combined therapy of CsA and anti-TNFα agents in rheumatoid arthritis Tumour necrosis factor α (TNFα) is a key cytokine in the integrated host defence system against infectious diseases. While clinical trials of anti-TNFα agents, in a number of AD, generally did not note increased susceptibility to typical or opportunistic infections, post-marketing analysis has clearly demonstrated an increased susceptibility to infections especially those caused by Mycobacterium tuberculosis, atypical mycobacteria as well as other intra-cellular organisms [22,23]. Considering also that TNFα blockers have to be given in combination with methotrexate, or other immunosuppressant agents, rheumatologist are refrained to use anti-TNFα in patients with AD and concomitant chronic HCV infection. On the other hand there are studies, dedicated to identify predictors of response to therapy in patients with HCV infection, that have suggested a central role for host factors in the outcome of therapy [24,25]. In particular, TNFα has been implicated in refractoriness to IFN therapy in HCV patients. The subject of the role of TNFα, and of the imbalance of h1/h2 T lymphocytes response, in the development of HCV chronic infection and in determining the refractoriness to antiviral therapies, has been recently reviewed by Calabrese et al. [26]. In acute selflimited HCV infection, circulating Th cells have been shown to predominantly produce IFNγ, suggesting a Th 1-like response [27]. Similarly, while patients who are able to spontaneously clear acute HCV infections have a strong Th 1 response without detectable Th 2 response, those who become chronically infected have a dominant Th 2 response [28]. Furthermore, very preliminary data
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are available on the use of existing anti-TNF agents in patients with chronic HCV infection that show the safety of these agents in this condition [29]. Concerning the treatment of patients with concomitant AD, a study of 24 patients with chronic HCV infection and rheumatoid arthritis, who received anti-TNF therapy (etanercept or infliximab), has been recently reported [30]. No significant adverse events were seen in these patients. No statistically significant changes were noted in the liver aminotransferases or in HCV-RNA viral loads yet 16/22 patients with pre-treatment and post-treatment HCV-RNA measurements showed decline in viral load [30]. A retrospective multicenter study, focused on the treatment of HCV-RNA positive RA subjects with antiTNFα agents, is ongoing in Italy (GISEA study group). Our personal contribution to this study is made of 6 patients and we can confirm the safety of the therapy in HCV infected patients with RA. Interestingly, in two of this patients anti-TNF were added to CsA because of its clinical and biological inefficacy. In one case, Adalimumab (Humira) was given at the standard dose of 40 mg every 2 weeks subcutaneously (s.c.), in the second Etanercept (Enbrel) was administrated s.c. at the dosage of 25 mg twice a week. These patients have been treated for 6 months and no detectable side effects were seen so far. Aminotransferases remained within normal limits and viral load did not increase. As far as we know this is the first report describing the safety of CsA and anti-TNF combined therapy in HCV positive RA patients. 6. Conclusions Autoimmune disorders and HCV chronic infection can frequently occur in the same patient. In this case, the treatment of AD may become difficult due to the well-known risk to worsen the HCV infection outcome with the use of corticosteroids and/or immunosuppressants. In fact, the experiences accumulated in transplanted patients clearly show that while a potent immunosuppressive regimen prevents allograft rejection, it also favours viral replication and facilitates viral-mediated graft injury. Recent in vitro studies together with clinical data have demonstrated that CsA has substantial antiviral activity. CsA can thus act as a dual-action drug by decreasing the activity of the immune system, thus avoiding graft rejection in transplanted patients and virus replication also in AD patients, and by interfering with viral replication that can lead in both cases, to the damage of the organ. Information in literature, concerning safety and efficacy
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of CsA in the treatment of HCV+ AD patients, is limited to few case reports, nevertheless evidence have been found that CsA can be safely used also in these conditions. Therefore, we can conclude that even if further prospective trials are required to confirm the efficacy and safety of CsA in HCV+ individuals, the available data are highly suggestive that the use of CsA contributes to better outcome also in patients affected by AD and concomitant HCV infection with or without CAH. Take-home messages •
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In vitro and in vivo studies, in liver transplanted patients and in patients with CAH, demonstrate that CsA exert an inhibitory effect on HCV replication. Preliminary studies suggest that CsA can be safely used in the treatment of patients affected by autoimmune disorders with concomitant chronic HCV infection.
References [1] Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001;35:666–78. [2] Wright TL, Donegan E, Hsu HH, Ferrell L, Lake JR, Kim M, et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterology 1992;103:317–22. [3] Chazouilleres O, Kim M, Combs C, Ferrell L, Bacchetti P, Roberts J, et al. Quantitation of hepatitis C virus RNA in liver transplant recipients. Gastroenterology 1994;106:994–9. [4] Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, Rayon M, et al. HCV-related fibrosis progression following liver transplantation: increase in recent years. J Hepatol Apr 2000;32 (4):673–84. [5] McCaughan GW. Immunosuppression for HCV following liver transplantation: enough is just enough. Transplantation 2004;78:1413–4. [6] Levy G, Villamil F, Samuel D, Sanjuan F, Grazi GL, Wu Y, et al. Results of LIS2T, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation. Transplantation 2004;77:1632–8. [7] Casanovas Taltavull T. Impact of cyclosporine on the development of immunosuppressive therapy in liver transplantation. Transplant Proc 2004;36:S291–4. [8] Kugelmas M, Osgood MJ, Trotter JF, Bak T, Wachs M, Forman L, et al. Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection. Liver Transpl 2003;9: 1159–65. [9] Ghobrial RM, Farmer DG, Baquerizo A, Colquhoun S, Rosen HR, Yersiz H, et al. Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center cells. Transplant Proc Dec 2005;37(10):4598–602. [10] Berenguer M, Crippin J, Gish R, Bass N, Bostrom A, Netto G, et al. A model to predict severe HCV-related disease following liver transplantation. Hepatology 2003;38:34–41.
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[11] Duvoux C, Mennecier D, Pageaux G. Immunosuppression with tacrolimus and absence of antihypertensive therapy are associated with fibrosis progression after hepatitis C virus graft reinfection. International society of transplantation congress; 2002. abs. 2652. [12] Nakamuta M, Kohjima M, Fukushima M, Morizono S, Kotoh K, Kobayashi N, et al. Cyclosporine suppresses cell growth and collagen production in hepatic stellate cells. Transplant Proc Dec 2005;37(10):4598–602. [13] Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol 2003;38:567–72. [14] Everson GT. Impact of immunosuppressive therapy on recurrence of hepatitis C. Liver Transpl 2002;8:19–27. [15] Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science Jul 2 1999;285 (5424):110–3. [16] Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003;38(5):1282–8. [17] Sebastiani GD, Bellisai F, Caudai C, Rottoli P, Valensin PE, Pippi L, et al. Association of extrahepatic manifestations with HLA class II alleles and with virus genotype in HCV infected patients. J Biol Regul Homeost Agents Jan–Jun 2005;19(1–2):17–22. [18] Galeazzi M, Manganelli S, Bellisai F, Gonnelli L. HCV e malattie autoimmuni. Riv It Biol Med 1996;16:91–101. [19] Miura H, Itoh Y, Matsumoto Y, Tani M, Tanabe N, Isonokami M, et al. Long-term administration of cyclosporin A to HCVantibody-positive patients with dermatologic diseases. Int J Dermatol Apr 1999;38(4):310–4. [20] Galeazzi M, Bellisai F, Sebastiani GD, Giannitti C, Garcia Gonzales E. Utilizzo della ciclosporina in pazienti HCV positivi. Reumatismo 2005;57(4):122–4 [numero speciale 3].
[21] Donvito A, Bellisai F, Morozzi G, Crisanti A, Galeazzi M. La ciclosporina A nel trattamento dei disordini autoimmuni in pazienti con infezione cronica da HCV: studio pilota in aperto. Reumatismo 2005;57(4):265 [(numero speciale 3) abstract C03]. [22] Safety update on TNF-α antagonists: infliximab and etanercept. Food and Drug Administration, Arthritis Drugs Advisory Committee, 17 August 2001. Available at: www.fda/gov/ ohrms/dockets/ac/01/transcripts/3779+2_01.pdf [accessed 29 July 2004]. [23] Ellerin T, Rubin RH, Weinblatt ME. Infections and anti-tumor necrosis factor alpha therapy. Arthritis Rheum 2003;48:3013–22. [24] Di Bisceglie AM, Hoofnagle JH. Optimal therapy of hepatitis C. Hepatology 2002;36:S121–7. [25] Lindsay KL. Introduction to therapy of hepatitis C. Hepatology 2002;36:S114–20. [26] Calabrese LH, Zein N, Vassilopoulos D. Safety of anti-tumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection. Ann Rheum Dis Nov 2004;63(Suppl 2):ii18–24. [27] Diepolder HM, Zachoval R, Hoffmann RM, Wierenga EA, Santantonio T, Jung MC, et al. Possible mechanism involving Tlymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 1995;346:1006–7. [28] Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC. Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity. Hepatology 1997; 25:449–58. [29] Zein NN. A phase II randomised, double blind, placebo controlled study of tumor necrosis factor antagonist (Etanercept, Enbrel) as an adjuvant to interferon and ribavirin in naive patients with chronic hepatitis C [abstract]. Hepatology 2002;36:504A. [30] Peterson JR, Hsu FC, Simkin PA, Wener MH. Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003;62:1078–82.
Autoimmune disease in asthma Previous research has suggested an inverse relationship between Th2-related atopic disorders, such as asthma, and Th1-related autoimmune diseases. In this study, Tirosh A, et al. (Ann Intern Med 2006; 144: 877-83) assessed the rate of newly diagnosed autoimmune disorders in a large cohort of young adults. Using cross-sectional data from the Israeli Defense Force database, the prevalence of autoimmune disorders was analyzed in asthmatic and nonasthmatic 307 367 male and 181 474 female military personnel between 1980 and 2003. Cases of type 1 diabetes mellitus, vasculitis, immune thrombocytopenic purpura, inflammatory bowel disease, rheumatoid arthritis, and the antiphospholipid syndrome were studied. Of 488 841 participants at enrollment, significantly more women than men had autoimmune disorders. Compared with asthmatic women, nonasthmatic women had a significantly higher prevalence of autoimmune disorders except for the antiphospholipid syndrome. During the follow-up period, vasculitis and rheumatoid arthritis were more frequently diagnosed in nonasthmatic persons of both sexes. There was a significant higher incidence of immune thrombocytopenic purpura, inflammatory bowel disease, and the antiphospholipid syndrome in nonasthmatic women and a statistically significantly higher incidence of type I diabetes mellitus in nonasthmatic men. Thus, asthma status may affect the prevalence of major autoimmune disorders. Preexisting asthma seems to protect against the development of autoimmune disorders to varying degrees in men and women.