A 36-year-old female presenting with swelling and tenderness in both the knees with abnormal Liver function test 

Discussion

The middle aged, female patient presented with episodic arthritis or arthralgia, predominantly in larger joints. She had no systemic features. Clinical evaluation revealed that the patient had elevated ESR suggestive of inflammatory arthritis. RF and ANA were normal; however she was positive for hepatitis B serology.

The episodic arthritis is usually seen in cases with immune complex arthritis, crystal-induced arthritis or palindromic rheumatism. The conditions like SLE, vasculitis, and seronegative spondyloarthropathy can initially present with episodic arthritis. Rarely, rheumatoid arthritis can present with intermittent arthritis. Crystal- induced arthritis like gout, pseudo gout, and infections like viral arthritis may present rarely as episodic arthritis, but chronic viral infections, especially hepatitis B, C, and HIV, can present with recurrent arthritis. Palindromic rheumatism is a diagnosis of exclusion.¹  Arthritis may be the only presentation of hepatitis B infection both in acute as well as in chronic stages. ^2,3

The incidence of extrahepatic manifestations of chronic hepatitis B is well described and its incidence differs between the series. The most common manifestation is acute, self-limiting, migratory arthritis, which is seen in more than 15-40% of the patients infected by HBV virus in the early infections. The percentage of patients with extrahepatic rheumatological manifestations is comparatively less with reference to HCV. In a series of 190 patients, thirty (16%) subjects had clinical extrahepatic manifestations, mainly sensory-motor deficiency, sicca syndrome, myalgia, glomerulonephritis, and arthralgia-arthritis. Their presence was not related to any epidemiologic, viral (including genotypes) or hepatic factor, but to an increased platelet count (P=0.004).  Twenty-nine (15%) patients had different auto-antibodies manifestations, mainly anti-smooth muscle, antinuclear, and anti-nucleosome antibodies. Their presence was related only to anti-HBe antibodies positivity (P=0.007) or elevated platelet count (P=0.003).⁴ The classically described polyarthritis nodusa (PAN) is less commonly seen in Asian population. Acute arthritis is seen in a significant proportion of HBV infected patients. However, only a few may have an initial presentation of persisting non-destructive arthritis. Glomerulonephritis which resolves spontaneously has been reported.in many is reported. Typical arthritis-dermatitis syndrome, seen in early phase of infection, presents with triad of purpura, arthritis and weakness. In certain subjects, it may persist to evolve into nephritis, pulmonary disease, or generalized vasculitis syndrome and acrodermatitis.^{5, 6} Association with cryoglobulinemia is not common in cases with HBV when compared to HCV. The infection with HBV and HCV may be associated with several autoantibodies. Increased prevalence of RF positivity in the absence of RA was noted in a study that assessed the prevalence of RF positivity in Korea among HBV-positive patients. The rates of RF positivity noted in healthy adults and subjects with HBsAg were 3.7 and 11.8%, respectively.⁷ Similarly, another study from India  also indicated the possibility of false positive RF and even anti-CCP in patients with HBV infection.⁸ Hence, it is preferable to evaluate anti-CCP and RF to confirm RA in the presence of HBV infection. The possibility of non-specific positivity of RF is higher in the presence of HBV infection.⁹ Anti-CCP is found to be the most useful serologic marker for the differentiation of RA and non-RA rheumatic diseases, and chronic viral hepatitis B and C.¹⁰ In a study looking at the detection possibility of HBV-associated arthralgia, the incidence did not significantly differ from the population prevalence of HBV infection.¹¹

The rheumatological symptoms are more in patients with HCV infection when compared to HBV. An Egyptian study reported the overall estimated prevalence of rheumatologic manifestations as 16.39% (chronic fatigue syndrome 9.5%, sicca symptoms 8.8%, arthralgia 6.5%, fibromyalgia 1.9%, myalgia 1.3%, arthritis 0.7%, cryoglobulinemic vasculitis 0.7%, autoimmune hemolytic anemia 0.7%, thrombocytopenia 0.7%). Xerophthalmia was significantly present in male population (p = 0.04).¹²

In order to adopt a different treatment approach, it is essential to make sure that the disease per se is due to hepatitis B rather than any autoimmune diseases. In the presence of HBV-producing rheumatological manifestations and other autoimmune diseases like PAN, it is recommended to use less of immune-suppressive and to depend more on antiviral therapy and plasmapheresis. There is evidence contradicting the use of traditional immune suppressive therapy and steroid in HBV PAN cases.¹³  

Clinical features, serological markers of hepatitis B, and autoantibody markers help us to differentiate between these two conditions. Presence of autoantibody in conjunction with HBV infections should be carefully interpreted.

References

1. Kaushik P. Palindromic rheumatism: a descriptive report of seven cases from North Dakota and a short review of literature. Clin Rheumatol. 2010 Jan;29(1):83-6.
2. Pease C, Keat A.  Arthritis as the main or only symptom of hepatitis B infection. Postgraduate medical journal 61.716 (1985): 545-547.
3. Shim  M, Han SHB. Extrahepatic manifestations of chronic hepatitis B. Hepatitis B Annual 3.1 (2006): 128.
4. Cacoub P, Saadoun D, Bourlière M, Khiri H, Martineau A, Benhamou Y, Varastet M, Pol S, Thibault V, Rotily M, Halfon P.Hepatitis B virus genotypes and extrahepatic manifestations. J Hepatol. 2005 Nov;43(5):764-70. Epub 2005 Jun 28.
5. Han SH. Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis. 2004 May;8(2):403-18.
6. Pyrsopoulos NT, Reddy KR.Extrahepatic manifestations of chronic viral hepatitis. Curr Gastroenterol Rep. 2001 Feb;3(1):71-8.
7. Shim CN, Hwang JW, Lee J, Koh EM, Cha HS, Ahn JK. 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 Nov;22(6):885-91.
8. Singh U, Verma PK, Bhagat P, Singh S, Singh S, Singh NK . IgG RF and anti-CCP2 antibody can be positive in undifferentiated arthritis due to streptococcal infection, hepatitis B virus, tuberculosis, trauma and hypothyroidism: a preliminary study. Rheumatol Int. 2012 Sep;32(9):2687-90. 26.
9. Zhou RF, Liu XF, Chen Y, Wu F, Zeng AP, Cheng YJ.  [Detection of antibodies to cyclic citrullinated peptides and its clinical significance in patients with chronic hepatitis B virus infection].[Article in Chinese] Zhonghua Yi Xue Za Zhi. 2012 Jun 12;92(22):1536-9.
10. Ryu HJ, Takeuchi F, Kuwata S, Kim YJ, Lee EY, Lee EB, Song YW The diagnostic utilities of anti-agalactosyl IgG antibodies, anti-cyclic citrullinated peptide antibodies, and rheumatoid factors in rheumatoid arthritis. Rheumatol Int. 2011 Mar;31(3):315-9. doi: 10.1007/s00296-009-1260-5. Epub 2009 Dec 15.
11. Varache S, Narbonne V, Jousse-Joulin S, Guennoc X, Dougados M, Daurès JP, Devauchelle-Pensec V, Saraux A. Is routine viral screening useful in patients with recent-onset polyarthritis of a duration of at least 6 weeks? Results from a nationwide longitudinal prospective cohort study. Arthritis Care Res (Hoboken). 2011 Nov;63(11):1565-70.
12. Mohammed RH, ElMakhzangy HI, Gamal A, Mekky F, El Kassas M, Mohammed N, Abdel Hamid M, Esmat G. Prevalence of rheumatologic manifestations of chronic hepatitis C virus infection among Egyptians. Clin Rheumatol. 2010 Dec;29(12):1373-80. doi: 10.1007/s10067-010-1463-x. Epub 2010 Apr 22.
13. Trepo C, Guillevin L. Polyarteritis nodosa and extrahepatic manifestations of HBV infection: the case against autoimmune intervention in pathogenesis. J Autoimmun. 2001 May;16(3):269-74.

Further reading on HBV

Ganem, Don, and Alfred M. Prince. "Hepatitis B virus infection—natural history and clinical consequences." New England Journal of Medicine 350.11 (2004): 1118-1129.

Lok, Anna SF, and Brian J. McMahon. "Chronic hepatitis B." Hepatology 45.2 (2007): 507-539.