Indian Journal of Rheumatology

: 2017  |  Volume : 12  |  Issue : 2  |  Page : 97--103

Diagnosis and management of rheumatic manifestations of Hepatitis B, Hepatitis C and immunodeficiency Virus

Arun Ramesh Chogle 
 Division of Rheumatology, Sir H. N. Reliance Foundation Hospital, Mumbai, Maharashtra, India

Correspondence Address:
Arun Ramesh Chogle
Division of Rheumatology, Sir H. N. Reliance Foundation Hospital, Raja Rammohan Roy Road, Mumbai - 400 004, Maharashtra


Hepatitis B, hepatitis C virus and human immunodeficiency virus infections are important causes of virally mediated arthritis. These can pose several diagnostic and therapeutic dilemmas. This review analyzes the recent publications on this topic and discusses the related issues on diagnosis and treatment.

How to cite this article:
Chogle AR. Diagnosis and management of rheumatic manifestations of Hepatitis B, Hepatitis C and immunodeficiency Virus.Indian J Rheumatol 2017;12:97-103

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Chogle AR. Diagnosis and management of rheumatic manifestations of Hepatitis B, Hepatitis C and immunodeficiency Virus. Indian J Rheumatol [serial online] 2017 [cited 2020 Jun 6 ];12:97-103
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Full Text

Cases of viral infection can present to a rheumatologist with joint pains. The rheumatic manifestations of hepatitis B virus (HBV), hepatitis C virus (HCV), with or without human immunodeficiency virus (HIV) coinfections can pose diagnostic, therapeutic challenges to the rheumatologist. In this review, we focus on the management strategies of such patients.

 Selection of Studies

A literature search was performed on MEDLINEE using the following key words; “hepatitis B”, “hepatitis C”, “cryoglobulinemai”, “diagnosis”, “guidelines”. “HIV”, ”therapeutics”. Peer-reviewed articles including review articles, observational studies and case reports published from 2014 were included in the review. References from these articles were manually searched and relevant articles weer also included in this review.

 Hepatitis B Virus

Arthritis occurs in two situations [Table 1]. In acute hepatitis, articular manifestations occur in the preicteric phase resembling rheumatoid arthritis (RA). Rheumatoid factor is positive in a quarter of such cases and is associated with low complement C3–C4 levels.[1]{Table 1}

Hepatitis B Virus - Polyarteritis Nodosa

HBV polyarteritis nodosa (PAN) is an example of vasculitis related to a viral agent [2] and is a severe disease requiring aggressive treatment. Plasma exchange (PE) helps in the removal of viral components including circulating immune complexes as well as blocking the replication and reactivation of HBV. Subsequent to use of PE, use of antiviral agents such as lamivudine helps in reducing viral loads. The newer antiviral agents such as adefovir dipivoxil, entecavir, telbivudine, and tenofovir are potentially useful for treatment of HBV PAN, but the trial evidence is lacking.[3]

Association of Hepatitis B Virus and Rheumatoid Arthritis

A study of 223 RA patients from China found no association between HBV and rheumatoid disease activity, synovitis, or joint destruction.[4] Further studies are necessary to confirm whether RA has a pathogenic association with HBV.

Hepatitis B Virus reactivation

This occurs in two forms:

Harmful proliferation of virus in hepatitis B surface antigen (HBsAg)-positive cases, healthy carriers or chronic HBV hepatitis.In cases of occult infection (HBsAg-negative and anti-HB virus core antibody-positive and anti-HB virus surface antibodies [HBsAbs] positive).

Immunosuppressants can induce HBV reactivation (HBVr). However, informative data regarding the risk of reactivation after the use of different immunosuppressive drugs (ISDs) including biologics are unsettled.

Two recent studies have investigated incidence and causes of HBVr in rheumatic diseases. The first is a multicenter prospective, observational study in Japan.[5] All ISDs including biologics, steroids, methotrexate (MTX), and synthetic disease-modifying antirheumatic drugs (sDMARDs) can cause HBVr. The risk of MTX causing HBVr was low as compared to studies from the USA possibly because the dose of MTX used for treating RA was lower in Japan as compared to the USA. Risk of reactivation was higher with prednisolone, low titers or negative HBsAb, and advanced age. A similar finding was noted in 2334 RA patients undergoing mono or combination immunosuppressive treatments.[6] Glucocorticoid in combination with biological DMARDs and sDMARDs had the highest risk of HBVr compared with the patients who received sDMARDs without steroids.

 Hepatitis C Virus

Known complications of chronic HCV infection include cirrhosis and liver cancer. However, a significant number of cases develop extrahepatic manifestations which affect various systems such as central and peripheral nervous system, musculoskeletal system, and endocrine systems and may present to the rheumatologist for the treatment. HCV-related rheumatic disorders are characterized by frequent clinico-serologic overlap, and correct diagnosis is necessary before therapeutic decisions are taken [Table 1].[7]

Arthralgia is a common, but chronic HCV-related arthritis (HCVrA) is less common. HCVrA is of two different clinical types: polyarthritis affecting smaller joints resembling RA and oligoarthritis affecting larger joints. The latter is often associated with the presence of serum cryoglobulins.[7] A case report described a patient on interferon therapy for HCV developing an RA-like polyarthritis and rheumatoid nodulosis.[8] HCVr is managed symptomatically with analgesics and nonsteroidal anti-inflammatory drugs.

Two update articles have reviewed the extrahepatic manifestations of HCV. First article is regarding immune-related manifestations of HCV [9] and second on oral manifestations.[10]

Cryoglobulinemia Vasculitis

Cryoglobulinemia vasculitis (CryoVas) is a small vessel vasculitis with several clinical manifestations such as purpura, arthralgia, and systemic involvement. CryoVas is associated with chronic infection, particularly HCV, autoimmune disorder, and B-cell lymphoma. An update on CryoVas has opined that to judge response to new therapeutic strategies, universal criteria are the need of the hour.[11]

To be classified as CryoVas at least two of the three items included in a questionnaire, clinical and laboratory items should be present.[12] These have a specificity (96.1%) in HCV-positive cases as compared to HCV-negative cases (90.3%). The management of CryoVas is based on the type of cryoglobulin and HCV status.

In Type II/III CryoVas, rituximab is effective, while in Type I CryoVas, it requires multidrug chemotherapy.[11]

Hepatitis C Virus - Polyarteritis Nodosa

PAN is another variety of HCV-related vasculitis. As opposed to HBV-PAN which clinically manifests <1 year after viral exposure, HCV-PAN occurs several years after viral exposure.[13]

Immune-related Manifestations of Hepatitis C Virus

HCV-associated immune-related syndromes affect various systems and organs and manifest as palpable purpura, kidney disease, peripheral neuropathy, and arthritis. Besides this, several autoantibodies have been detected whose clinical significance is doubtful.[9]

Oral and Cutaneous Manifestations of Hepatitis C Virus

The oral manifestations include oral lichen planus (OLP) and Sjogren's syndrome. The virus may cause OLP by replicating in the oral mucosa and attracting HCV-specific T-lymphocyte. Even in the absence of symptoms, patients frequently have histological signs of Sjogren-like sialadenitis. However, it is still unclear if HCV is directly responsible for this.[10] Cutaneous manifestations include palpable purpura, seen in cases of mixed CryoVas, lichen planus, and psoriasis.


This includes antiviral drugs and symptomatic treatments. Interferon-based regimens have limited effectiveness and are poorly tolerated.[14] The new direct antiviral agents (DAAs) have better safety profile. Since only one DAA, sofosbuvir, is available in India, the Indian National Association for Study of the Liver recommends two sofosbuvir-based regimens: sofosbuvir in combination with ribavirin for 6 months or sofosbuvir with ribavirin and pegylated interferon for 3 months.[15]

Monitoring Rheumatic Patients with Hepatitis B Virus/Hepatitis C Virus

Several guidelines from prominent societies are available. However, common themes across these guidelines are lacking. The American Gastroenterological Association has stratified the risk of HBVr as high, moderate, and low [Figure 1].[16]{Figure 1}

The American College of Rheumatology (ACR) published recommendations in 2008, 2012, and 2015 for the treatment of RA. The 2008 guidelines recommended screening for HBV in high-risk patients, particularly in parenteral drug users or those with high-risk sexual activity before starting MTX and leflunomide. The recommendations are stratified as per Child-Turcotte-Pugh (CTP) score classes (A, B, or C), based on the albumin, total bilirubin levels, and presence of ascites and encephalopathy. Patients with score of >10 are classified as Class C while those with lower scores are classified as classified Class A or B.

MTX is contraindicated in all CTP score classes (A, B, or C). Sulfasalazine is less hepatotoxic than MTX and is only contraindicated in CTP scores B or C. AS per the 2012 ACR recommendations, etanercept can be used in RA patients with hepatitis C.

The 2015 ACR guidelines include treatment recommendations for RA patients with high-risk co-morbidities such as hepatitis. These recommendations are graded as strong or conditional.[17]

Provided antiviral therapy is prescribed concomitantly for RA with HBV, and immunosuppressive therapy can be safely used (strong recommendation).

For RA with HCV, the recommendation is conditional, and collaboration with hepatologist and rheumatologist is suggested. Tumor necrosis factor-α (TNF-α) inhibitors can be used if the treatment with antiviral therapy is prescribed. Rest should receive DMARDS other than MTX or leflunomide such as sulfasalazine or hydroxychloroquine [Figure 2].{Figure 2}

The 2015 ACR criteria have been criticized for not including newer standards for hepatitis B screening.[18] Several international and national societies of different specialties have published guidelines for screening and monitoring rheumatic patients with coexisting HBV/HCV infection. Future guidelines to be published by these societies should agree on and disseminate a cohesive front.[18]

Biological Disease-modifying Antirheumatic Drugs

Anti-TNF-α drugs are used to treat several rheumatic diseases and are associated with HBVr. A recent study found that 39% of the 257 HBsAg-positive cases receiving anti-TNF-α drugs reported HBVr. Infliximab often causes HBVr as compared to etanercept. This is explained by pharmacological differences between these molecules.[19]

In case of rituximab, HBVr has occurred up to 1 year after stopping this drug.[20]

Cytokine inhibitors – abatacept (anti-CD80-86) and ustekinumab (anti-IL12/23) – have been associated with HBVr and documented in case reports.[21]

 Human Immunodeficiency Virus

In the early stages of HIV epidemic, patients with AIDS had painful, disabling asymmetrical inflammatory arthropathy.[22] With the introduction of highly active antiretroviral therapy (HAART) in 1995, various newer musculoskeletal disorders are described.[23] A review article has described the change in pattern of rheumatic disease in HIV.[24] [Table 2] mentions the areas of agreement and controversy on this topic.{Table 2}

Reactive Arthritis in Human Immunodeficiency Virus

Typically, this presents as a case of rheumatoid factor negative oligoarthritis with enthesitis. Mucocutaneous features include keratodermia blenorraghicum and circinate balanitis. Axial involvement and uveitis occur in human leukocyte antigen B27-positive individuals.[25]

Reports from African countries have reported increased incidence of reactive arthritis in HIV-positive individuals. In contrast, this is rare in Asian countries. Further investigations can define the roles of immunogenicity and environmental factors.[24]

Some of the earlier known rheumatic manifestations, HIV infection, particularly spondyloarthropathy and diffuse infiltrative lymphocytosis syndrome, and vasculitis have shown a decreasing incidence after HAART. On the other hand, there is increasing incidence of osteopenia and osteonecrosis, particularly in patients on prolonged HAART. This is due to metabolic effects of this therapy. Mitochondrial toxicity is seen with nucleoside reverse transcriptase inhibitors and manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis.[26]

The molecular mimicry between HIV protein and self-antigens causes antibody cross-reactions and development of autoimmune disease. HIV also causes an imbalance in T-lymphocytes, with depletion of CD4+ cells and a relative increase in CD8+ cells.

This has an adverse effect on the selection of self-reactive antibody repertoires contributing to development of autoimmune disease. This phenomenon has been described as immune reconstitution inflammatory syndrome.[27]

RA can develop in HIV cases at any time, irrespective of HAART. Hydroxychloroquine and sulfasalazine are used in such cases. Corticosteroids may also be used when HIV replication is controlled with HAART.[28]

Formal guidelines regarding safety of DMARDs in HIV patients with RA are still not available. Limited information regarding use of TNF-α inhibitors in HIV-infected patients with RA is available but none regarding rituximab, tocilizumab, or abatacept.[28]

Monitoring RA disease activity in HIV cases remains challenging. There is only one publication on this topic. This has shown that DAS28-erythrocyte sedimentation rate (ESR) is a less reliable measure of disease activity than the DAS28-C-reactive protein because of the nonspecific increase in ESR with HIV infection.[29]

 Hepatitis C Virus and B Virus Coinfection in Human Immunodeficiency Virus

The clinical course of HIV may be complicated by the presence of coinfection with HBV and HCV. These coinfections have an impact on rheumatic manifestations and complicate the management of such cases. Such cases have been reported from Eastern India.[30] Further multicenter studies from various parts of the country are needed to assess the pattern of HIV/HBV/HCV coinfection in India.

 Hepatitis C Virus/human Immunodeficiency Virus Coinfection

Few published studies on this topic are available. A cross-sectional study found that HCV monoinfected patient more commonly reported arthralgia as compared to HCV/HIV-coinfected patients. This could possibly due to several reasons. Higher tolerance of HIV-infected patients who give higher priority to other HIV-related serious complications and immune dysfunction related to HIV, which leads to decreased effect of inflammation, resulting from HCV deposition in periarticular structures and joints.[31]

Skeletal fragility in HIV/HCV-coinfected patients is due to many causes and includes HIV-related inflammation, antiretroviral therapy-related cytotoxicity, and inflammatory cytokines associated with chronic HCV. Previous studies have used dual-energy X-ray absorptiometry which cannot identify distinct defects in trabecular and cortical bone mass. A recent study used tibial peripheral quantitative computed tomography for assessing trabecular volumetric base mineral density. This study has found that HIV/HCV-coinfected women had significant cortical bone loss. Similar studies are required in HIV/HCV-coinfected men and also in cases following antiviral therapy.[32]

A recent review indicated that Vitamin D is a relatively inexpensive therapeutic option to lower HCV-related fracture risk. Other determinants of HCV-related increased fracture risk have still to be defined.[33]


Choosing DMARD therapy for the management of rheumatic diseases in the presence of chronic viral hepatitis with or without HIV coinfections is a challenging task for clinicians. Several guidelines from prominent societies are available. However, in the future, there is necessity of common themes across these guidelines and gaps in current knowledge should be assessed.


I thank Dr. Radhika Wandrekar for her assistance in manuscript editing.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Marks M, Marks JL. Viral arthritis. Clin Med (Lond) 2016;16:129-34.
2Teng GG, Chatham WW. Vasculitis related to viral and other microbial agents. Best Pract Res Clin Rheumatol 2015;29:226-43.
3Sharma 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;3:204-12.
4Zou CJ, Zhu LJ, Li YH, Mo YQ, Zheng DH, Ma JD, et al. The association between hepatitis B virus infection and disease activity, synovitis, or joint destruction in rheumatoid arthritis. Clin Rheumatol 2013;32:787-95.
5Fukuda W, Hanyu T, Katayama M, Mizuki S, Okada A, Miyata M, et al. Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: A multicentre, prospective, observational study in Japan. Ann Rheum Dis 2016. pii: Annrheumdis-2016-209973.
6Chen MH, Chen MH, Liu CY, Tsai CY, Huang DF, Lin HY, et al. Hepatitis B virus reactivation in rheumatoid arthritis patients undergoing biologics treatment. J Infect Dis 2016. pii: jiw606.
7Palazzi C, D'Amico E, D'Angelo S, Gilio M, Olivieri I. Rheumatic manifestations of hepatitis C virus chronic infection: Indications for a correct diagnosis. World J Gastroenterol 2016;22:1405-10.
8Wen H, Schumacher HR, Pullman-Mooar SW, Einhorn E. Unusual draining nodules in a patient with rheumatoid nodulosis and hepatitis C virus infection. J Rheumatol 2011;38:1806-8.
9Tampaki M, Koskinas J. Extrahepatic immune related manifestations in chronic hepatitis C virus infection. World J Gastroenterol 2014;20:12372-80.
10Carrozzo M, Scally K. Oral manifestations of hepatitis C virus infection. World J Gastroenterol 2014;20:7534-43.
11Terrier B, Cacoub P. Cryoglobulinemia vasculitis: An update. Curr Opin Rheumatol 2013;25:10-8.
12De Vita S, Soldano F, Isola M, Monti G, Gabrielli A, Tzioufas A, et al. Preliminary classification criteria for the cryoglobulinaemic vasculitis. Ann Rheum Dis 2011;70:1183-90.
13Saadoun D, Terrier B, Semoun O, Sene D, Maisonobe T, Musset L, et al. Hepatitis C virus-associated polyarteritis nodosa. Arthritis Care Res (Hoboken) 2011;63:427-35.
14Calabrese LH, Cacoub PP. For patients with rheumatic disease and hepatitis C infection: The end of interferon. RMD Open 2015;1:e000008.
15Puri P, Anand AC, Saraswat VA, Acharya SK, Dhiman RK, Sarin SK, et al. Indian National Association for Study of the Liver (INASL) guidance for antiviral therapy against HCV infection in 2015. J Clin Exp Hepatol 2015;5:221-38.
16Pattullo V. Prevention of hepatitis B reactivation in the setting of immunosuppression. Clin Mol Hepatol 2016;22:219-37.
17Singh JA, Saag KG, Bridges SL Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2016;68:1-25.
18Calabrese LH, Calabrese C, Kirchner E. The 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis should include new standards for hepatitis B screening. Arthritis Rheumatol 2016;68:1314-5.
19Pérez-Alvarez R, Díaz-Lagares C, García-Hernández F, Lopez-Roses L, Brito-Zerón P, Pérez-de-Lis M, et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: Analysis of 257 cases. Medicine (Baltimore) 2011;90:359-71.
20Felis-Giemza A, Olesinska M, Swierkocka K, Wiesik-Szewczyk E, Haladyj E. Treatment of rheumatic diseases and hepatitis B virus coinfection. Rheumatol Int 2015;35:385-92.
21Koskinas JS, Deutsch M, Adamidi S, Skondra M, Tampaki M, Alexopoulou A, et al. The role of tenofovir in preventing and treating hepatitis B virus (HBV) reactivation in immunosuppressed patients. A real life experience from a tertiary center. Eur J Intern Med 2014;25:768-71.
22Winchester R, Bernstein DH, Fischer HD, Enlow R, Solomon G. The co-occurrence of Reiter's syndrome and acquired immunodeficiency. Ann Intern Med 1987;106:19-26.
23Kole AK, Roy R, Kole DC. Musculoskeletal and rheumatological disorders in HIV infection: Experience in a tertiary referral center. Indian J Sex Transm Dis 2013;34:107-12.
24Lawson E, Walker-Bone K. The changing spectrum of rheumatic disease in HIV infection. Br Med Bull 2012;103:203-21.
25Adizie T, Moots RJ, Hodkinson B, French N, Adebajo AO. Inflammatory arthritis in HIV positive patients: A practical guide. BMC Infect Dis 2016;16:100.
26Marfatia YS, Talwar M, Sharma A, Mehta K. Mitochondrial toxicities of nucleoside of analogue reverse transcriptase inhibitors in AIDS cases. Indian J Sex Transm Dis 2014;35:96-9.
27Fox C, Walker-Bone K. Evolving spectrum of HIV-associated rheumatic syndromes. Best Pract Res Clin Rheumatol 2015;29:244-58.
28Carroll MB, Fields JH, Clerc PG. Rheumatoid arthritis in patients with HIV: Management challenges. Open Access Rheumatol 2016;8:51-59.
29Tarr G, Makda M, Musenge E, Tikly M. Effect of human immunodeficiency virus infection on disease activity in rheumatoid arthritis: A retrospective study in South Africans. J Rheumatol 2014;41:1645-9.
30Chakravarty R, Pal A. Insights into human immunodeficiency virus-hepatitis B virus co-infection in India. World J Virol 2015;4:255-64.
31Ogdie A, Pang WG, Forde KA, Samir BD, Mulugeta L, Chang KM, et al. Prevalence and risk factors for patient-reported joint pain among patients with HIV/hepatitis C coinfection, hepatitis C monoinfection, and HIV monoinfection. BMC Musculoskelet Disord 2015;16:93.
32Lo Re V 3rd, Lynn K, Stumm ER, Long J, Nezamzadeh MS, Baker JF, et al. Structural bone deficits in HIV/HCV-coinfected, HCV-monoinfected, and HIV-monoinfected women. J Infect Dis 2015;212:924-33.
33Di Carlo P, Siracusa L, Mazzola G, Colletti P, Soresi M, Giannitrapani L, et al. Vitamin D and osteoporosis in HIV/HCV coinfected patients: A literature review. Int J Endocrinol 2015;2015:969040.