|Year : 2018 | Volume
| Issue : 4 | Page : 229-232
Clinical utility of anti-cyclic citrullinated peptid and rheumatoid factor in chronic hepatitis B virus infection
Gokhan Sargin1, Altay Kandemir2
1 Department of Rheumatology, Adnan Menderes University, Aydin, Turkey
2 Department of Gastroenterology, Adnan Menderes University, Aydin, Turkey
|Date of Web Publication||18-Nov-2018|
Dr. Gokhan Sargin
Department of Rheumatology, Adnan Menderes University, Aydin
Source of Support: None, Conflict of Interest: None
Background: It is necessary to distinguish whether musculoskeletal symptoms are associated with rheumatic diseases or hepatitis virus infection. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) may be detected in rheumatic diseases and also during infections. The objective of this study was to evaluate the clinical utility of anti-CCP and RF in patients with chronic hepatitis B virus (HBV) infection.
Methods: Ninety-seven patients with chronic HBV infection, 35 patients with rheumatoid arthritis (RA), and 30 healthy controls were included in the study. HBV-DNA, hepatitis B e antigen, anti-HBe, RF, and anti-CCP were evaluated.
Results: The rates of positivity for RF and anti-CCP were 14.4% and 4.1% respectively in patients with chronic HBV infection. Arthritis was present in 7 of 97 patients with chronic HBV infection. There was a statistically significant difference for anti-CCP positivity but not for RF positivity between patients with arthritis and without arthritis. No correlation was found between RF and anti-CCP, HBV-DNA, anti-CCP, and HBV-DNA in patients with HBV infection.
Conclusions: Anti-CCP positivity was a determinant for polyarthritis in the context of HBV infection. It appears to be a more reliable parameter than RF in differentiating arthritis and nonarthritis group in patients with HBV infection.
Keywords: Anti-cyclic citrullinated, clinical significance, hepatitis B, rheumatoid factor
|How to cite this article:|
Sargin G, Kandemir A. Clinical utility of anti-cyclic citrullinated peptid and rheumatoid factor in chronic hepatitis B virus infection. Indian J Rheumatol 2018;13:229-32
|How to cite this URL:|
Sargin G, Kandemir A. Clinical utility of anti-cyclic citrullinated peptid and rheumatoid factor in chronic hepatitis B virus infection. Indian J Rheumatol [serial online] 2018 [cited 2019 Sep 16];13:229-32. Available from: http://www.indianjrheumatol.com/text.asp?2018/13/4/229/241790
| Introduction|| |
Hepatitis B virus (HBV) is a partially double-stranded DNA virus and may lead to different clinical presentations such as acute, fulminant, or chronic hepatitis. HBV infection remains a global public health problem despite the availability of an effective vaccine. It is estimated that 248 million people are chronic carriers and almost two billion people worldwide are infected with HBV., The prevalence of HBV infection varies according to the geographical area and observed in the different parts of the world ranging from 0.1% to 20%.
Chronic HBV carriers may develop complications including liver cirrhosis and hepatocellular carcinoma. Articular manifestations resembling rheumatoid arthritis (RA) occur in acute hepatitis. In chronic HBV infection, there may be musculoskeletal symptoms such as arthralgia and polyarthritis as in rheumatic diseases.
Some clinical signs and symptoms may mimic RA in chronic viral HBV infection. It is important to distinguish between both clinical disorders. In this case, the rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) used in the classification of RA may be helpful. RF positivity has been shown in RA, Sjogren's syndrome and systemic sclerosis., RF and anti-CCP were reported higher in HBV infection patients with RA than healthy controls. Furthermore, anti-CCP may be useful to differentiate HBV-associated arthropathy from patients with RA and chronic HBV infection.
The aim of the study was to evaluate the clinical utility of anti-CCP and RF in patients with chronic HBV infection. In addition, the relationship between these antibodies and viral load and the rates of RF and anti-CCP positivity were investigated in chronic HBV infection.
| Methods|| |
Ninety-seven patients (33 males and 64 females, with the mean age of 48 ± 12.6) with chronic HBV infection, 35 patients with RA who were followed regularly in our outpatient clinics, and 30 healthy controls were enrolled in this study. Patients with a history of infections except for HBV, malignancy, and any rheumatic disease other than RA were not included in the study.
Chronic HBV infection was diagnosed with HBsAg positivity for >6 months, HBV-DNA levels above 104 copies/mL, and elevated serum transaminase levels. Patients were defined as inactivated HBV carriers if there was no viral replication despite HBV infection (HBV-DNA <2000 IU/mL, negative HBeAg with anti-HBe positivity, and normal serum transaminase levels). The 2010 American College of Rheumatology (ACR) classification criteria were used to classify RA. Joints with pain, tenderness, swelling, and stiffness were defined as arthritis. The distal interphalangeal, first metacarpophalangeal, and first metatarsophalangeal joints were not evaluated for the RA diagnosis. The patients with a score of 6/10 according to the 2010 ACR classification criteria, patients with typical radiographic erosive lesions for RA are classified as having RA.
Age, sex, HBV-DNA, HBeAg, anti-HBe, RF, and anti-CCP were evaluated, retrospectively. Anti-CCP was analyzed using an enzyme-linked immunosorbent assay method in accordance with the manufacturer's recommended guidelines, and the latex fixation test was used to measure RF. Both RF and anti-CCP samples at the high concentration measured again after serial dilution. Patients with values <18 IU/ml were considered negative for RF, and values >4.99 U/ml for anti-CCP were considered as positive.
The PASW for Windows version 17.0 (Statistical Package for the Social Sciences version 17.0, Inc., Chicago, IL, USA) was used for statistical analysis. Kolmogorov–Smirnov test was used to determine the distribution of normality. The data were presented as the number of patients (n), mean ± standard deviation, median (minimum–maximum), and percentages (%) according to the distribution of normality. Chi-square test, Kruskal–Wallis test, Mann–Whitney U-test, and two-way ANOVA test were used for statistical analyses. Spearman's correlation test was used for statistical analysis and assessed by Spearman's rho correlation coefficient. The data were examined at the confidence level of 95%, and P < 0.05 was accepted as statistically significant.
This study was approved by the ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.
| Results|| |
Table shows demographics and disease related characteristics. Sixty-four patients with chronic HBV infection, 28 RA patients, and 25 individuals of the healthy group were female. There was no statistical difference in age and gender between all groups. The rates of positivity for RF and anti-CCP were 14.4% and 4.1% in patients with chronic HBV infection, respectively. RF positivity was detected in 14 of 97 patients with HBV infection and 10% in the healthy group. Of the 35 patients with RA, 23 were positive for RF, and 25 were positive for anti-CCP. Moreover, no anti-CCP positivity was detected in the healthy group. The rate of RF positivity was higher in RA patients than in patients with chronic HBV infection and healthy group (P < 0.001).
The demographic and clinical characteristics of patients with chronic HBV infection, RA, and healthy group are shown in [Table 1]. The median RF value was higher in patients with RA compared to patients with chronic HBV infection and healthy group (P < 0.001). The rate of anti-CCP positivity was higher in patients with chronic HBV infection and RA patients compared to the healthy group. There was no statistical correlation between RF positivity and HBeAg and RF positivity and Anti-Hbe.
|Table 1: The demographic characteristics of patients with chronic Hepatitis B virus infection, rheumatoid arthritis, and healthy group|
Click here to view
Arthritis was present in 7 of 97 patients with chronic HBV infection. We detected RF and anti-CCP positivity in 14.4% and 4.1% of patients with HBV infection, respectively. There was a statistically significant difference for anti-CCP positivity but not for RF positivity between patients with arthritis and patients without arthritis [Table 2]. Four patients with HBV infection had polyarthritis, two patients had oligoarthritis, and one had monoarthritis. All anti-CCP levels in patients with polyarthritis were positive. Four of them fulfilled the ACR classification criteria for RA, and the duration of the symptom of arthritis was over 6 weeks. Arthritis was not detected in the healthy group. The correlation was found between RF and anti-CCP titers. There was no correlation between RF and anti-CCP, RF and HBV-DNA value, anti-CCP and HBV-DNA value in patients with HBV infection.
|Table 2: The distribution of rheumatoid factor, anti-cyclic citrullinated peptide and viral markers in chronic hepatitis B virus patients with and without arthritis|
Click here to view
| Discussion|| |
This study was aimed to identify the clinical significance of anti-CCP and RF in patients with chronic HBV infection. In our study, we found the anti-CCP and RF positivity in patients with chronic HBV infection and the healthy group as in RA. There was a statistical significance for anti-CCP positivity in HBV patients with arthritis compared to nonarthritic patients. However, it was not applied to RF positivity.
Extrahepatic manifestations other than hepatic may be observed in HBV infection. The polyarthritis is an one of the extrahepatic clinical findings in HBV patients, more closely related to the acute form. Furthermore, polyarthritis may occur in patients with chronic HBV. It is believed to be associated with the immunocomplex, and it may be difficult to distinguish whether polyarthritis is due to HBV infection or to RA. HBV is implicated in the pathogenesis of RA. Arthropathy mimicking RA has been reported to occur in 10%–35% of HBV infections. In our study, seven patients with HBV infection had arthritis, and ninety patients were without any joint symptoms. Corticosteroid, hydroxychloroquine, and methotrexate started in polyarthritis patients with polyarthritis who met the 2010 RA classification criteria considering HBV-DNA and transaminases.
RF and anti-CCP play an important role in the diagnosis of polyarthritis and are included in the classification criteria for RA. However, the antibodies positivity alone do not meet the 2010 RA classification criteria. Although the frequency of RF was reported as 70%–90% in RA, it can be detected in patients with other rheumatic diseases Sjogren's syndrome, systemic sclerosis, and also during hepatitis infections. IgG, IgA, and IgM RF were detected in 21%, 29.5%, and 18.8% of HBV patients without arthritis. According to this study, there was no association between these antibodies and anti-CCP. RF positivity may probably due to chronic stimulation of the immune system. It has been reported that RF is not very useful for differentiating RA in patients with concurrent hepatitis infection. Because RF can be detected positively in 20%–75% of patients with chronic HBV infection. In our study, we detected RF and anti-CCP positivity in 14.4% and 4.1% of patients with HBV infection. RF positivity rates may vary according to the geographical distribution of infectious agents. There are conflicting studies about the association between age, gender, and RF positivity. The correlation between titer of HBV-DNA, and RF has been reported in chronic HBV infection. In another study, RF titer was reported as higher in HBsAg-positive patients than in HBsAg-negative patients. RF was positive in 15.38% of HBe antigen-positive patients and 14.63% of HBe antigen-negative patients. The ratio of RF positivity of the anti-HBe-positive group was reported higher than the anti-HBe antibody-negative group. In this study, there was no statistically significant correlation between viral load and both of these autoantibodies and also the correlation between RF positivity and HBeAg, RF positivity, and anti-Hbe.
Anti-CCP is reported more specific serological marker for RA. However, the marker may be seen at different rates in infections such as tuberculosis, HIV, and hepatitis B and C. Anti-CCP was detected in 0%–20.5% of patients with HBV infections., Zengin et al. have determined 20.5% of anti-CCP positivity with low titer in HBV patients without any symptoms. We detected anti-CCP positivity in three (3%) patients in HBV patients with arthritis and 1% in patients without arthritis. Anti-CCP is used to distinguish HBV-associated arthropathy from concomitant RA in patients with chronic HBV infection. Lee et al. evaluated anti-CCP as a useful diagnostic marker to exclude RA in chronic HBV infection. They reported anti-CCP positivity with low titer in only one patient (0.6%) in chronic HBV infection without arthritis. Therefore, anti-CCP may be a useful test to diagnose the RA in patients with chronic HBV infection due to weakly positivity. In our study, anti-CCP positivity was 42.9% in patients with HBV infection with arthritis, whereas anti-CCP was found in only one patient who had no any symptoms. In another study by Dalkılıc et al., anti-CCP has been reported to be an important marker for differential diagnosis in RF-positive HBV infections. The anti-CCP positivity was detected in only one patient with chronic HBV patients, and there was no correlation between RF and anti-CCP. It was thought that anti-CCP was not specifically produced in response to HBV infection due to no correlation with RF. Anti-CCP is useful than RF in discriminating RA patients in chronic HBV infection and for the differential diagnosis in RF-positive HBV infections.,
Anti-CCP positivity was determinant for polyarthritis due to rarely detected in HBV infection. We detected a significant difference for anti-CCP between patients with arthritis and patients without arthritis. However, there was no significant difference for RF in both groups. The limitation of our study is that we have no information about the changes in RF and anti-CCP titers with the treatment in patients with HBV infection, and it is difficult to know which patient will develop RA in long-term follow-up. Based on this study, it appears that anti-CCP is a more reliable parameter than RF in differentiating arthritis and nonarthritis group in patients with HBV infection.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000;64:51-68.
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012;30:2212-9.
Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet 2015;386:1546-55.
Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology 2009;50:661-2.
Trépo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet 2014;384:2053-63.
Chogle AR. Diagnosis and management of rheumatic manifestations of hepatitis B, hepatitis C and immunodeficiency virus. Indian J Rheumatol 2017;12:97-103. [Full text]
Morita Y, Muro Y, Sugiura K, Tomita Y. Anti-cyclic citrullinated peptide antibody in systemic sclerosis. Clin Exp Rheumatol 2008;26:542-7.
Feist E, Burmester GR. Laboratory tests in rheumatic disorders. In: Hochberg MC, Gravallese EM, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology. Philadelphia: Elsevier Inc.; 2018. p. 257-62.
Zhou RF, Liu XF, Chen Y, Wu F, Zeng AP, Cheng YJ, et al.
Detection of antibodies to cyclic citrullinated peptides and its clinical significance in patients with chronic hepatitis B virus infection. Zhonghua Yi Xue Za Zhi 2012;92:1536-9.
Lim MK, Sheen DH, Lee YJ, Mun YR, Park M, Shim SC, et al.
Anti-cyclic citrullinated peptide antibodies distinguish hepatitis B virus (HBV)-associated arthropathy from concomitant rheumatoid arthritis in patients with chronic HBV infection. J Rheumatol 2009;36:712-6.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd
, et al
. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69:1580-8.
Baig S, Alamgir M. The extrahepatic manifestations of hepatitis B virus. J Coll Physicians Surg Pak 2008;18:451-7.
Csepregi A, Nemesanszky E, Rojkovich B, Poor G. Rheumatoid arthritis and hepatitis B virus: Evaluating the pathogenic link. J Rheumatol 2001;28:474-7.
Lee SI, Yoo WH, Yun HJ, Kim DS, Lee HS, Choi SI, et al.
Absence of antibody to cyclic citrullinated peptide in sera of non-arthritic patients with chronic hepatitis B virus infection. Clin Rheumatol 2007;26:1079-82.
Ingegnoli F, Castelli R, Gualtierotti R. Rheumatoid factors: Clinical applications. Dis Markers 2013;35:727-34.
Shim CN, Hwang JW, Lee J, Koh EM, Cha HS, Ahn JK, et al.
Prevalence of rheumatoid factor and parameters associated with rheumatoid factor positivity in korean health screening subjects and subjects with hepatitis B surface antigen. Mod Rheumatol 2012;22:885-91.
Choi ST, Lee HW, Song JS, Lee SK, Park YB. Analysis of rheumatoid factor according to various hepatitis B virus infectious statuses. Clin Exp Rheumatol 2014;32:168-73.
Yeh HM, Chiang W, Chen SF, Dai SM, Shin NH, Wu CS, et al.
Rheumatoid factor in hepatitis B virus surface antigen positive patients. Gaoxiong Yi Xue Ke Xue Za Zhi 1994;10:239-43.
Lima I, Santiago M. Antibodies against cyclic citrullinated peptides in infectious diseases – A systematic review. Clin Rheumatol 2010;29:1345-51.
Zengin O, Yıldız H, Demir ZH, Dağ MS, Aydınlı M, Onat AM, et al.
Rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies with hepatitis B and hepatitis C infection: Review. Adv Clin Exp Med 2017;26:987-90.
Dalkılıç E, Öksüz MF, Tufan AN, Özbek A, Nizamoğlu A, Dolarslan ME, et al.
Anti-cyclic citrullinated peptide and rheumatoid factor in patients with chronic hepatitis B and hepatitis B carriers. Eur J Rheumatol 2015;2:62-5.
[Table 1], [Table 2]