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Original article 1

Treatment with Peg-IFNa2a/ribavirin and low-dose NSAID for patients with chronic hepatitis C and rheumatoid syndrome
Georgiana C. Lilea, Costin T. Streba, Cristin C. Vere and Ion Rogoveanu
Objective To examine the safety and efficiency of using Peg-IFNa2a/ribavirin and low-dose NSAID therapy in patients with rheumatoid syndrome (RS) and chronic hepatitis C (CHC). Methods A group of 10 patients (group 1) known to have RS and established CHC undergoing Peg-IFNa2a/ribavirin and low-dose NSAID therapy was compared with a control group of 10 patients (group 2) also with CHC and associated RS, with no antiviral treatment. Their charts were reviewed for serological and clinical signs of rheumatic disease evolution while undergoing this type of treatment. Results At the end of a follow-up period of 12 months, patients receiving low-dose NSAID and Peg-IFNa2a/ ribavirin therapy showed a sustained virusological response and also decreased levels of inflammation serological markers, with an improvement in the clinical rheumatic symptoms. In contrast, patients in group 2 showed no significant clinical modification in their rheumatic status. Conclusion Peg-IFNa2a/ribavirin and low-dose NSAID in patients with RS and CHC appear to be well tolerated and can be efficient for rheumatic manifestations. Further controlled studies are required to confirm the c 2012 results. Eur J Gastroenterol Hepatol 00:000000 Wolters Kluwer Health | Lippincott Williams & Wilkins.
European Journal of Gastroenterology & Hepatology 2012, 00:000000 Keywords: hepatitis C, NSAID, Peg-IFNa2a/ribavirin, rheumatoid syndrome Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Craiova, Romania Correspondence to Costin T. Streba, MD, PhD, Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, St. Petru Rares No 2-4, 200349 Craiova, Romania Tel: + 40 722 389 906; fax: + 40 251 310 287; e-mail: costinstreba@gmail.com Received 27 February 2012 Accepted 13 August 2012

Introduction
Hepatitis C virus (HCV), an enveloped positive-stranded RNA virus of the genus Hepacivirus spp. and family Flaviviridae, is an important epidemiological medical problem worldwide with a high rate of infectivity and a significant risk for the infected individuals to develop chronic hepatitis [1]. The association between HCV and autoimmune disorders is present in daily clinical practice. Laboratory investigations carried out in HCV-affected patients may indicate a large number of autoantibodies, including anticardiolipin antibodies, rheumatoid factor, smooth muscle antibodies, antiparietal cell antibodies, antiliver/kidney microsomal antibodies type I, and antineutrophil cytoplasmic antibodies [24]. Researchers have suggested various mechanisms to explain the association between HCV and autoimmunity, taking into consideration the role of chronic hepatitis C (CHC) in several autoimmune or immune mediated conditions such as rheumatoid arthritis, sicca syndrome, mixed cryoglobulinemia, pan arteritis nodosa, HCVrelated arthritis, myasthenia gravis, and psoriatic arthritis. Reports show that 0.655.4% of patients with rheumatoid syndrome (RS) have been identified as carriers of the HCV [5]. A huge number of these patients need to be treated with corticosteroids often in association with antiviral agents
c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 0954-691X

but this type of therapy is problematic because of the well-known fact that corticoid treatment has many sideeffects. The mechanism of action of the huge majority of NSAIDs is to nonselectively inhibit the cyclooxygenase (COX) enzyme, effecting both the COX-1 and COX-2 isoenzymes. COX is involved in the formation of prostaglandins and thromboxane from arachidonic acid and prostaglandins modulate the inflammation process. Interferon-a (IFN-a) is well known for its role in the treatment of CHC, in particular in association with ribavirin. Another efficient role of IFN-a treatment in HCV infection relates to the clinical manifestations of cryoglobulinemia [6]. However, the involvement of IFNa therapy in other rheumatologic manifestations associated with CHC has rarely been investigated. In this article, we focused on the role of the combination between IFN-a/ribavirin and low-dose NSAID in the treatment of RS patients who are also affected by CHC infection. We aimed to investigate whether this therapy could be safe and efficient for rheumatic disease besides the impact on viral infection.

Patients and methods

Twenty female patients with both RS and CHC (genotype 1) were recruited in our study, aged 3050 years. Patients were admitted in the Department of
DOI: 10.1097/MEG.0b013e32835948c1

2 European Journal of Gastroenterology & Hepatology 2012, Vol 00 No 00

Gastroenterology of the Emergency County Hospital of Craiova between 1 July 2010 and 31 December 2010 and they were included in our study at the beginning of January 2011. Their symptoms and blood tests were reviewed 3 months and 12 months after the inclusion in the study by reviewing their medical charts. The disease duration was 710 years for HCV and 35 years for RS. Ten of them (group 1) received IFN-a therapy for a period of 12 months. The rest of the patients (group 2) refused the antiviral treatment. All patients provided informed consent (see attachment) for their inclusion, as well as all the procedures and treatments used during this study. We also obtained the approval of the ethic committees of the Emergency County Hospital of Craiova and of the University of Medicine and Pharmacy of Craiova. Inclusion criteria were as follows: viral load greater than 1 000 000 IU/ml, minimal liver cytolysis, negative rheumatoid factor, negative anticitrullinated peptide (anti-CCP) antibodies, slight elevation in serological inflammation markers, pain complaint in maximum three peripheral symmetrical joints with morning stiffness for less than 30 min, and no radiological modifications. All patients underwent intermittent treatment with a minimal dose of NSAID (Coxibs) when required, maximum 5 days/month. Patients in group 1 also received 180 mg Peg-IFNa2a and 8001000 mg/day of ribavirin according to their body weight. Liver function tests plus serum HCV-RNA load and inflammation serological markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] were checked for both groups at the beginning of treatment, 3 months later, and at the end of therapy by reviewing their medical charts. Tables 1 and 2 show the evolution of ESR and CRP during therapy.

There were a small number of values for the two parameters in the two groups that were registered at three different time points and they did not always follow a normal, Gaussian distribution. Therefore, we decided to test the differences between the means using the parametric analysis of variance (ANOVA) test and also the nonparametric KruskalWallis test.

Results
Sustained virusological response, normal levels of liver cytolysis enzymes as well as absent joint pain complaint were found in all 10 patients treated with Peg-IFNa2a/ ribavirin at the end of the 12 months of therapy. In terms of ESR in group 1, we identified a highly significant difference between the means of the values registered at three different moments (initial, 3 months of therapy, 12 months of therapy) both by ANOVA (P < 0.0001) and by the KruskalWallis test (P < 0.0001). Further analysis showed significant differences between certain times of evaluation: initial3 months; initial12 months; and 312 months. No significant difference was found in group 2 in the ESR values using both tests (P = 0.189366 and 0.898, respectively). Figure 1 shows the outcome of the therapy during the 12 months for the two groups in terms of the ESR levels. With respect to CRP in group 1, we identified a highly significant difference between the means of the values registered at three different time points (initial, 3 months of therapy, 12 months of therapy) both by ANOVA (P < 0.0001) and by the KruskalWallis test (P < 0.0001). Further analysis showed significant differences between certain time points of evaluation: initial3 months; 312 months.

Table 1

Evolution of ESR and C-reactive protein during therapy

Initial 562.17 160.99 3 months 302.28 110.9 12 months 200.99 3.50.44

Fig. 1

group 1
Parameters ESR CRP

ESR Group I Start 3 months 12 months 60

Initial 582.22 161.11 3 months 451.91 15.51.03 12 months 551.84 151.53

Group II 53.70

54.50 40 20 32.50 19.30 0

Values are presented as meansSD. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

49.10 49.80 20 40 60

Table 2

Evolution of ESR and C-reactive protein during therapy

group 2
Parameters ESR CRP

Values are presented as meansSD. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Outcome of the therapy during the 12 months for the two groups in terms of ESR levels. Values are presented as mm/h (*ANOVA test, P < 0.0001). ANOVA, analysis of variance; ESR, erythrocyte sedimentation rate.

PegIFN/ribavirin and NSAID in HCV and RS Lilea et al. 3

Fig. 2

CRP Group I Start 3 months 12 months 20 15 10 15.50 10.90 5 5.04 0 Group II 15.70 15.70 14.80 5 10 15 20

for this type of associated pathology involves problematic aspects taking into consideration that IFN-a therapy is also involved in the development of autoimmune dysfunction [10]. Nevertheless, starting from the premise that autoimmune diseases including rheumatoid arthritis involve immune reactions against specific antigens, Ying et al. [11] investigated the role of type I IFN in antigeninduced arthritis in mice and reached the conclusion that type I IFN can prevent joint inflammation by downregulating antigen-specific cellular immunity. In our study, 10 patients with both CHC and RS received IFN-ribavirin in association with intermittent low-dose NSAID for a period of 12 months. Minimal cytolysis levels allowed us to use NSAIDs at a minimal dose, only 5 days/month. The positive effect was indicated by the satisfactory results at the end of the 12-month period for all 10 patients who underwent this type of therapy. Besides experimental arthritis, it was established that IFNs can influence gastrointestinal inflammatory diseases, and also allergic encephalomyelitis and neonatal inflammation [12]. This can be considered as evidence for the anti-inflammatory role of IFN, which has been investigated poorly until recently. It has not yet been clarified why only certain tissues respond to the antiinflammatory functions of IFN [13]. Some data suggest that it can benefit inflammatory disease because of its effect on the cytokine cascade [14]. Dinarello [15] provided evidence of the anti-inflammatory properties of IFN-a by reporting a reduction in interleukin-1 (IL-1) and phorbol myristate acetate-induced IL-1 synthesis by IFN-a. However, Abu-Khabar et al. [16] reported that IFN-a suppresses tumor necrosis factor-a gene expression and protein synthesis in vitro. Moreover, there is proof of the induction on IL-10 by IFN-a mostly pronounced in activated CD4 cells [17]. Costimulation with LPS had a huge impact in terms of the effect of IFN-a on IL-10 in purified monocytes, all these biological reactions participating in the anti-inflammatory mechanism of IFN-a [14]. Glisslinger et al. [18] presented another conclusive theory for the anti-inflammatory and immunosuppressive function of IFN-a such as its ability to stimulate the hypothalamicpituitaryadrenal axis in vitro and in vivo. The hematological impact of IFN-a should also be considered. Administration of IFN-a leads to suppression of hematopoiesis in vivo [19] and, in the case of inflammatory disease, this suppression of hematopoiesis may trigger a limited supply of mature effector cells and thus a reduced inflammatory process [14]. As a result of the new discoveries, the efficiency of type 1 IFNs can be improved by yet another therapeutic property of IFNs such as their important activity as mediators of anti-inflammatory responses. In our study, we suspect the immunoregulatory and anti-inflammatory activity of the IFN-a to play a major role in decreasing the

Outcome of the therapy during the 12 months for the two groups in terms of CRP levels. Values are presented as mg/l (*ANOVA test, P < 0.0001). ANOVA, analysis of variance; CRP, C-reactive protein.

No significant difference was found in group 2 in the CRP values using both tests (P = 0.808276 and 0.898, respectively). Figure 2 shows the outcome of the therapy along the 12 months for the two groups in terms of the CRP levels.

Discussion
In this study, we present an analysis of 20 patients with documented RS and CHC. Ten of them were subjected to a 12-month therapy of Peg-IFNa2a/ribavirin and intermittent low-dose NSAID. A sustained virusological response was obtained, as well as normal levels of liver cytolysis enzymes. Moreover, the therapy was efficient for the articular symptoms and was well tolerated. IFN-a in combination with ribavirin has yielded positive results in the treatment of CHC but research data on the role of this therapy with respect to the rheumatologic manifestations associated with CHC are scarce. Recently, several studies have examined the role of IFN and its combination with other drugs in various pathological situations, including the association between CHC and RS. It was found that treatment with IFN-a may led to a marked clinical improvement in HCV-related arthritis even without a complete biochemical or virusological response [7]. In a study of 21 HCV-positive patients presenting rheumatoid arthritis symptoms, a beneficial clinical response to IFN-a therapy was found in 76% of cases, although 43% of patients had detectable cryoglobulin, and so a mixed cryoglobulinemia diagnosis could have been made for many of these patients [8]. The association of methotrexate and IFN-a therapy in HCV-positive patients who also had rheumatologic disorders could be considered for difficult cases [9]. We were reluctant to use methotrexate because of its hematological side-effects such as anemia, thrombocytopenia, and leukopenia. The use of this antiviral treatment

4 European Journal of Gastroenterology & Hepatology 2012, Vol 00 No 00

inflammation marker levels and to improve joint symptoms in all patients in the test group, whereas controls showed no alteration in their rheumatic status. The limitations of our study were the reduced number of patients, further tests on larger groups being necessary to confirm the results. We did not encounter any sideeffects of the antiviral therapy and no indication of altered rheumatic manifestations, therefore indicating the safety and beneficial clinical effect of this combination in the treatment of patients with CHC and RS.
Conclusion

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The association between CHC and RS implies many therapy issues. IFN-a is well known for its role in the treatment of CHC, particularly in association with ribavirin, but its anti-inflammatory functions have only recently been investigated. Peg-IFNa2a/ribavirin and low-dose NSAID in patients with RS and CHC appear to be well tolerated and can be efficient for rheumatic manifestations. Our analysis contributes with new information that can improve the management of patients affected by CHC and RS, further controlled studies being required to confirm the results.

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Acknowledgements
Georgiana C. Lilea acknowledges the support received as a PhD student within the project Doctorate an Attractive Research Career, contract number POSDRU/ID/88/1.5/ S/52826 co-financed by European Social Fund through Sectoral Operational Programme for Human Resources Development 20072013.
Conflicts of interest

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There are no conflicts of interest.

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