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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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
hepatitis C; NSAID; Peg-IFNα2a/ribavirin; rheumatoid syndrome