Articol Lilea.pdf

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Treatment with Peg-IFNa2a/ribavirin and low-dose NSAID forpatients 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 haveRS and established CHC undergoing Peg-IFNa2a/ribavirin

and low-dose NSAID therapy was compared with a controlgroup of 10 patients (group 2) also with CHC and

associated RS, with no antiviral treatment. Their chartswere reviewed for serological and clinical signs of

rheumatic disease evolution while undergoing this typeof treatment.

ResultsAt 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

results. Eur J Gastroenterol Hepatol 00:000000 c 2012Wolters 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 ofCraiova, 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, 200349Craiova, RomaniaTel: + 40 722 389 906; fax: + 40 251 310 287; e-mail: [email protected]

Received 27 February 2012 Accepted 13 August 2012

IntroductionHepatitis 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 investiga-

tions carried out in HCV-affected patients may indicate a

large number of autoantibodies, including anticardiolipinantibodies, rheumatoid factor, smooth muscle antibodies,

antiparietal cell antibodies, antiliver/kidney microsomal

antibodies type I, and antineutrophil cytoplasmic anti-

bodies [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 mediatedconditions such as rheumatoid arthritis, sicca syndrome,

mixed cryoglobulinemia, pan arteritis nodosa, HCV-

related 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].

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 isoen-

zymes. COX is involved in the formation of prostaglan-

dins and thromboxane from arachidonic acid and

prostaglandins modulate the inflammation process.

Interferon-a (IFN-a) is well known for its role in thetreatment 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 IFN-a therapy in other rheumatologic manifestations asso-

ciated 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 methodsTwenty female patients with both RS and CHC

Original article 1

CE: Jayashree ED: Asra Op: ananth MEG 201813: LWW_MEG_201813
mailto:[email protected]:[email protected]


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Gastroenterology of the Emergency County Hospital of

Craiova between 1 July 2010 and 31 December 2010 andthey were included in our study at the beginning of

January 2011. Their symptoms and blood tests werereviewed 3 months and 12 months after the inclusion in

the study by reviewing their medical charts. The diseaseduration 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 rheuma-

toid 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 aminimal dose of NSAID (Coxibs) when required,

maximum 5 days/month. Patients in group 1 also received

180 mg Peg-IFNa

2a and 8001000 mg/day of ribavirinaccording to their body weight.

Liver function tests plus serum HCV-RNA load and

inflammation serological markers [erythrocyte sedimenta-

tion 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 atthree different time points and they did not always follow

a normal, Gaussian distribution. Therefore, we decided totest the differences between the means using the

parametric analysis of variance (ANOVA) test and alsothe nonparametric KruskalWallis test.

ResultsSustained virusological response, normal levels of liver

cytolysis enzymes as well as absent joint pain complaintwere 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 betweencertain 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 bet-

ween certain time points of evaluation: initial3 months;312 months.

Table 1 Evolution of ESR and C-reactive protein during therapy group 1

Parameters Initial 3 months 12 months

ESR 562.17 302.28 200.99CRP 160.99 110.9 3.50.44

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

Table 2 Evolution of ESR and C-reactive protein during therapy group 2

Parameters Initial 3 months 12 months

ESR 582.22 451.91 551.84CRP 161.11 15.51.03 151.53

Fig. 1

Start 54.50 53.70

49.10

49.8019.30

60 40 20

ESR

0 20 40 60

32.503 months

12 months

Group I Group II

Outcome of the therapy during the 12 months for the two groups interms of ESR levels. Values are presented as mm/h (*ANOVA test,P < 0 0001) ANOVA analysis of variance; ESR erythrocyte

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


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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 12months for the two groups in terms of the CRP levels.

DiscussionIn 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 livercytolysis 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 pathologicalsituations, 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 presentingrheumatoid 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

for this type of associated pathology involves problematic

aspects taking into consideration that IFN-a therapy isalso involved in the development of autoimmune

dysfunction [10]. Nevertheless, starting from the premisethat autoimmune diseases including rheumatoid arthritis

involve immune reactions against specific antigens, Yinget 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 down-

regulating antigen-specific cellular immunity.

In our study, 10 patients with both CHC and RS received

IFN-ribavirin in association with intermittent low-doseNSAID 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 dis-

eases, and also allergic encephalomyelitis and neonatal

inflammation [12]. This can be considered as evidencefor 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-a by reporting a reduction in interleukin-1 (IL-1)

and phorbol myristate acetate-induced IL-1 synthesis byIFN-a. However, Abu-Khabar et al. [16] reported that

IFN-a suppresses tumor necrosis factor-a gene expres-

sion 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 ofIFN-a on IL-10 in purified monocytes, all these biological

reactions participating in the anti-inflammatory mechan-ism of IFN-a [14]. Glisslinger et al. [18] presented

another conclusive theory for the anti-inflammatory andimmunosuppressive function of IFN-a such as its ability

to stimulate the hypothalamicpituitaryadrenal axisin vitro and in vivo.

The hematological impact of IFN-a should also be

considered. Administration of IFN-a leads to suppressionof hematopoiesis in vivo [19] and, in the case of

inflammatory disease, this suppression of hematopoiesismay 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,

Fig. 2

Start

3 months

12 months

20 2015 1510

15.50

CRP

10.90

5.04 14.80

15.70

15.70

105 50

Group I Group II

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

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


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inflammation marker levels and to improve joint symp-

toms in all patients in the test group, whereas controlsshowed 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 combina-

tion in the treatment of patients with CHC and RS.

ConclusionThe 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 patientsaffected by CHC and RS, further controlled studies being

required to confirm the results.

AcknowledgementsGeorgiana 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 ResourcesDevelopment 20072013.

Conflicts of interest

There are no conflicts of interest.

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