Journals | Policy | Permission

This journal has moved to cii.elmerpub.com Please go to the new site to make submissions

Clinical Infection & Immunity

Original Article

Volume 3, Number 3-4, November 2018, pages 69-73

Evaluation of Rheumatologic Manifestations in Patients With Hepatitis B Infection and Their Relation to Hepatitis B Virus Activity

Human hepatitis B virus (HBV) infection leads to a wide range of liver diseases, such as acute and chronic hepatitis, hepatocellular carcinoma, and cirrhosis [1]. It is estimated that 350 million individuals are infected with hepatitis B virus [2]. In Iran the prevalence of HBV infection is about 2% and around 1.2 million of Iranian people are HBV infected [3]. Hepatitis B virus infection causes extrahepatic manifestations of which rheumatologic diseases are the most important. Although the exact mechanisms for these manifestations are not entirely understood, it appears that immune complexes play an important role in the development of these symptoms. A temporary serum sickness-like syndrome (SSS) is seen in 10-20% of patients with acute HBV infection [4]. The pathogenesis of SSS is due to circulating immune complexes including hepatitis B surface antigen (HBsAg) and complement consumption [5]. Rheumatoid factor (RF) is often positive and C3 and C4 are low in 40% of them, which express an immune-complex-mediated process [6, 7].

Polyarteritis nodosa (PAN) is a medium vessel vasculitis also related to HBV infection with annual prevalence of 4.6 to 77 per 1,000,000 hepatitis B patients [8]. The main manifestations of HBV associated with PAN are fever, arthralgia, malaise, weight loss, hypertension, ulcers and peripheral vascular manifestations. Formation of complexes of HBsAg and anti HBs antibodies and the deposition of these immune complexes in the vessel wall may result in vascular injury [9, 10]. Fibromyalgia (FM) is a syndrome with fatigue, musculoskeletal pain, sleep disturbance, and morning stiffness [11]. The prevalence of FM is about 25% in patients with HBV infection. It is believed that synthesis of inflammatory products or cytokines, such as interferon-alpha during HBV infection leads to development of FM. In addition the anxiety related to HBV infection may develop FM in these patients [12, 13].

Essential mixed cryoglobulinemia (EMC) with the clinical symptoms of arthritis, purpura, and kidney involvement, is associated with HBV infection. The prevalence of EMC is 15% in HBV patients [14]. It is believed that the immunological factors play a role in pathophysiology of rheumatic manifestations. Recognition of these symptoms is very important to facilitate early diagnosis and treatment of the disease [15-17]. According to the considerable prevalence of HBV infection in our country and the lack of strong evidences about rheumatologic manifestations of HBV, we designed this study to identify rheumatologic manifestations of HBV and their relation to HBV activity based on clinical and laboratory markers.

This cross-sectional study was performed on 250 HBV patients who were referred to the Hepatitis Clinic of Imam Khomeini Hospital during 1 year. The inclusion criteria were age of more than 18 years old and the presence of acute HBV infection (HBsAg positive or HBsAb positive or negative with positive HBcAg (IgM) or chronic infection with presence of HBsAg for more than 6 months with or without HBeAg and HBeAb).

Patients suffering from any other serious illness or concurrency of infection with other diseases such as hepatitis C, autoimmune hepatitis and HIV were excluded from the study.

The aim of the study was explained to the patients and a written consent was taken. In addition to the clinical evaluation, we used a questionnaire to collect information about age, gender, viral markers, laboratory tests results, clinical status, time of disease onset, severity of symptoms and type of drug. If there was any sign of rheumatologic involvement in these patients, they were referred to an expert rheumatologist for further evaluation.

The data were analyzed using SPSS version 20. Student’s t-test, χ² test, and Fisher exact test were used to compare the data. Results were significant at P < 0.05 and the confidence interval was 95%.

Seventy (28%) patients out of 250 were suffered from arthralgia. There was no significant relation between the stage of HBV infection and the arthralgia. Arthralgia was more frequent in inactive stage of HBV infection (45.7%) and more frequent in female than male (P = 0.001). In addition, 24% of patients were in precore mutant phase of HBV infection. The prevalence of serum sickness syndrome and fibromyalgia was 3.2% and 0.4% among HBV patients respectively. Demographic data and variables related to arthralgia and serum sickness syndrome are demonstrated in Tables 1 and 2.

Click to view

Table 1. The Demographic Features and Variables Related to Arthralgia

Click to view

Table 2. The Demographic Features and Variables Related to Serum Sickness Syndrome

The prevalence of rheumatoid factor (RF) in patients was 6%. Although 46.7% of RF positive patients were in inactive phase of the HBV, we couldn’t find any significant relation between RF and the HBV phase. The prevalence of anti-nuclear antibody (ANA) seropositivity was 5.2%. The mean ANA titer was 17.8 ± 5.2 (normal 10 to 27), and 53.8% of ANA positive patients were at inactive phase of HBV but no significant correlation was seen between the stages of HBV and ANA positive (P > 0.7). The prevalence of anti-cyclic citrullinated peptide (anti CCP) titer > 5 IU/mL was 18% in patients, and 54.5% were in inactive stage of the HBV. The relation between anti CCP titer > 5 IU/mL and the HBV stage was not significant (P > 0.08, Table 3). The prevalence of anti-dsDNA positive was only 0.03%. The frequency of patients with anti-ds DNA > 30 IU was higher in inactive phase of HBV and no significant relation was found with stages of HBV (P = 0.515).

Click to view

Table 3. The Demographic Features and Variables Related to Patients With Anti CCP Titer > 5 IU/mL

In our study the prevalence of SSS among patients with HBV was 3.2%. In Sergent’s study SSS was detected in 10 to 30% HBV patients [18]. It seems that circulating immune complexes including HBsAg and anti-HBs along with consumption of complement components were the main reason of SSS [5]. Alpert et al showed that 28% of HBV patients suffered from arthralgia [19] and Willson et al reported the presence of arthralgia in patients with HBV infection which was consistent with our study [20]. In the study of Ozsahin et al fibromyalgia was more common in HBV patients (22%) [13]. Adak et al also found an increased risk of fibromyalgia in chronic hepatitis B carries [21]. However, the prevalence of FM in our study was lower than the similar study.

In acute hepatitis B infection the viral antigens may present in circulation for many weeks and then the immune complexes will appear in the serum. Patients may produce antibody against the HBsAg and RF against IgG of immune complexes [22]. Choi et al, have revealed that the presence of HBV infection is an important cause for the positive RF in HBV endemic regions [23]. In the current study the occurrence of RF was 6%. However Hoofnagle et al reported 58.6% of HBV patients were RF positive in comparison to control group [24]. Regarding to the antinuclear antibodies (ANA) which is characterized by the presence or absence of special antibodies [25], we could find ANA seropositivity in 5.2% of our patients but there was not significant relation between ANA and age, gender, HBeAg, HBeAb, viral load, ALT and AST. Anti-citrullinated peptide antibody (ACPA) which has diagnostic role for rheumatoid arthritis [26] was positive in 18% of our HBV patients, but our study didn’t show any significant relation between ACPA and age, gender, HBeAg, HBeAb, viral load, ALT and AST. Studies demonstrated that anti-dsDNA has predictive value for diagnosis of systematic lupus erythematous [27, 28].

In the present study the prevalence of anti-dsDNA was 0.03%, and we couldn’t find any correlation between anti-dsDNA and age, gender, HBeAg, HBeAb, viral load, ALT and AST. According to our findings, it seems that careful examination of these patients is necessary for disease detection. We recommended further laboratory investigation in highly suspected rheumatic patients.

In the current research, the most frequent rheumatic diseases related to HBV infection were SSS, rheumatoid arthritis, arthralgia, PAN, and fibromyalgia. It is believed that the immunological factors play a role in pathophysiology of rheumatic manifestations. Recognition of these symptoms is very important to facilitate early diagnosis and treatment of the disease [15-17]. However, for better interpretations of the results multicenter cohort studies should be performed. In addition, it seems that the different variations of HBV genotype may be important and should be considered for future studies.

Author Contributions

Raheleh Namdar: study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript; Taraneh Dormohammadi Toosi: analysis and interpretation of data, statistical analysis, drafting of the manuscript, critical revision of the manuscript for important intellectual content, study supervision, corresponding author; Abdolrahman Rostamyan: study supervision, administrative and technical support; Shafieh Movassaghi: acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content; Mohsen Nassiri Toosi: acquisition of data, analysis and interpretation of data, critical revision of the manuscript for important intellectual content and hepatology consultant; Fatemeh Shahbazi: acquisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content.

Funding

This study was supported by Tehran University of Medical Science, research code: 92-02-30-21512.

Conflict of Interest

The authors declare that they have no conflict of interest.

1. Hollinger FB, Sood G. Occult hepatitis B virus infection: a covert operation. J Viral Hepat. 2010;17(1):1-15.
   doi pubmed
2. Eftekhari Y, Kazemi Arababadi M, Hakimi H, Rezazadeh Zarandi E. Common HBV genotype in southeastern Iranian patients. Arch Iran Med. 2010;13(2):147-149.
   pubmed
3. Alavian SM, Hajarizadeh B, Ahmadzad-Asl M, Kabir A, Bagheri-Lankarani K. Hepatitis B Virus infection in Iran: A systematic review. Hepat Mon. 2008;8(4):281-294.
4. Hollinger FB, Lau DT. Hepatitis B: the pathway to recovery through treatment. Gastroenterol Clin North Am. 2006;35(2):425-461, x.
   doi pubmed
5. Wands JR, Mann E, Alpert E, Isselbacher KJ. The pathogenesis of arthritis associated with acute hepatitis-B surface antigen-positive hepatitis. Complement activation and characterization of circulating immune complexes. J Clin Invest. 1975;55(5):930-936.
   doi pubmed
6. Vassilopoulos D, Calabrese LH. Virally associated arthritis 2008: clinical, epidemiologic, and pathophysiologic considerations. Arthritis Res Ther. 2008;10(5):215.
   doi pubmed
7. Inman RD. Rheumatic manifestations of hepatitis B virus infection. Semin Arthritis Rheum. 1982;11(4):406-420.
   doi
8. McMahon BJ, Heyward WL, Templin DW, Clement D, Lanier AP. Hepatitis B-associated polyarteritis nodosa in Alaskan Eskimos: clinical and epidemiologic features and long-term follow-up. Hepatology. 1989;9(1):97-101.
   doi pubmed
9. Sharma A, Sharma K. Hepatotropic viral infection associated systemic vasculitides-hepatitis B virus associated polyarteritis nodosa and hepatitis C virus associated cryoglobulinemic vasculitis. J Clin Exp Hepatol. 2013;3(3):204-212.
   doi pubmed
10. Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y. Infection and vasculitis. Rheumatology (Oxford). 2009;48(5):475-482.
    doi pubmed
11. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38(1):19-28.
    doi pubmed
12. Goldenberg DL. Do infections trigger fibromyalgia? Arthritis Rheum. 1993;36(11):1489-1492.
    doi pubmed
13. Ozsahin M, Gonen I, Ermis F, Oktay M, Besir FH, Kutlucan A, Sahin A, et al. The prevalence of fibromyalgia among patients with hepatitis B virus infection. Int J Clin Exp Med. 2013;6(9):804-808.
    pubmed
14. Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M, Grippon P, et al. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106(5):1291-1300.
    doi
15. Mori S. Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs. Mod Rheumatol. 2011;21(6):621-627.
    doi pubmed
16. Kappus MR, Sterling RK. Extrahepatic manifestations of acute hepatitis B virus infection. Gastroenterol Hepatol (N Y). 2013;9(2):123-126.
17. Yazmalar L, Deveci O, Batmaz I, Ipek D, Celepkolu T, Alpayci M, Hattapoglu E, et al. Fibromyalgia incidence among patients with hepatitis B infection. Int J Rheum Dis. 2016;19(7):637-643.
    doi pubmed
18. Sergent JS, Lockshin MD, Christian CL, Gocke DJ. Vasculitis with hepatitis B antigenemia: long-term observation in nine patients. Medicine (Baltimore). 1976;55(1):1-18.
    doi
19. Alpert E, Isselbacher KJ, Schur PH. The pathogenesis of arthritis associated with viral hepatitis. Complement-component studies. N Engl J Med. 1971;285(4):185-189.
    doi pubmed
20. Willson RA. Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol. 1997;92(1):3-17.
    pubmed
21. Adak B, Tekeoglu I, Ediz L, Budancamanak M, Yazgan T, Karahocagil K, Demirel A. Fibromyalgia frequency in hepatitis B carriers. J Clin Rheumatol. 2005;11(3):157-159.
    doi pubmed
22. Markenson JA, Daniels CA, Notkins AL, Hoofnagle JH, Gerety J, Barker LF. The interaction of rheumatoid factor with hepatitis B surface antigen-antibody complexes. Clin Exp Immunol. 1975;19(2):209-217.
    pubmed
23. 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(2):168-173.
    pubmed
24. Hoofnagle JH, Markenson JA, Daniels CA, Gerety RJ, Notkins AL, Barker LF. The lack of association between rheumatoid factor and hepatitis B antigen. Am J Med Sci. 1974;268(1):23-29.
    doi pubmed
25. Yamaguchi K, Fukushima H, Uzawa H. Response of human growth hormone, prolactin and thyrotropin to thyrotropin releasing hormone in liver cirrhosis and diabetes mellitus. Endocrinol Jpn. 1979;26(1):81-88.
    doi pubmed
26. Aggarwal R, Liao K, Nair R, Ringold S, Costenbader KH. Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum. 2009;61(11):1472-1483.
    doi pubmed
27. Arbuckle MR, James JA, Kohlhase KF, Rubertone MV, Dennis GJ, Harley JB. Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus. Scand J Immunol. 2001;54(1-2):211-219.
    doi pubmed
28. Swaak AJ, Groenwold J, Bronsveld W. Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis. 1986;45(5):359-366.
    doi pubmed

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinical Infection and Immunity is published by Elmer Press Inc.