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 2–4.
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, HCV-related arthritis, myasthenia gravis, and psoriatic arthritis.
Reports show that 0.65–5.4% 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 but this type of therapy is problematic because of the well-known fact that corticoid treatment has many side-effects.
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-α (IFN-α) is well known for its role in the treatment of CHC, in particular in association with ribavirin. Another efficient role of IFN-α treatment in HCV infection relates to the clinical manifestations of cryoglobulinemia 6. However, the involvement of IFN-α 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-α/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 30–50 years. Patients were admitted in the Department of 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 at 3 months and 12 months respectively after inclusion in the study by reviewing their medical charts. The disease duration was 7–10 years for HCV and 3–5 years for RS.
Ten of them (group 1) received IFN-α 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-IFNα2a and 800–1000 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 Kruskal–Wallis test.
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-IFNα2a/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 Kruskal–Wallis test (P<0.0001).
Further analysis showed significant differences between certain times of evaluation: initial–3 months; initial–12 months; and 3–12 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 Kruskal–Wallis test (P<0.0001).
Further analysis showed significant differences between certain time points of evaluation: initial–3 months; 3–12 months.
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.
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-IFNα2a/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-α 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-α may lead 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-α 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-α 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 for this type of associated pathology involves problematic aspects taking into consideration that IFN-α 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 antigen-induced 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 anti-inflammatory 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-α by reporting a reduction in interleukin-1 (IL-1) and phorbol myristate acetate-induced IL-1 synthesis by IFN-α. However, Abu-Khabar et al. 16 reported that IFN-α suppresses tumor necrosis factor-α gene expression and protein synthesis in vitro. Moreover, there is proof of the induction on IL-10 by IFN-α mostly pronounced in activated CD4 cells 17. Co-stimulation with LPS had a huge impact in terms of the effect of IFN-α on IL-10 in purified monocytes, all these biological reactions participating in the anti-inflammatory mechanism of IFN-α 14. Gisslinger et al. 18 presented another conclusive theory for the anti-inflammatory and immunosuppressive function of IFN-α such as its ability to stimulate the hypothalamic–pituitary–adrenal axis in vitro and in vivo.
The hematological impact of IFN-α should also be considered. Administration of IFN-α 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-α to play a major role in decreasing the 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 side-effects 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.
The association between CHC and RS implies many therapy issues. IFN-α 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-IFNα2a/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.
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 2007–2013.
Conflicts of interest
There are no conflicts of interest.
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