Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases

Best Practice & Research Clinical Rheumatology xxx (2015) 1e24

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Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases Worawit Louthrenoo* Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand

a b s t r a c t Keywords: Autoimmune rheumatic diseases Arthritis Virus Reactivation Immunosuppressive drugs Anti-TNFa

Widespread use of immunosuppressive drugs, both conventional disease-modifying antirheumatic drugs (cDMARDs) and biologic disease-modifying antirheumatic drugs (bDMARDs), in autoimmune rheumatic diseases (ARDs) has been found to be associated with the reactivation of underlying latent viruses. The clinical features of virus reactivation can sometimes mimic flare of the underlying ARDs. The correct diagnosis and management of such reactivation is crucial, as increasing the dose of immunosuppressive drugs to treat a presumed flare of underlying ARDs would probably be of no benefit, and it could exert a detrimental effect on the host. This review focused on the effects of immunosuppressive drugs on underlying chronic viral infections, particularly hepatitis B virus, hepatitis C virus, human immunodeficiency virus, varicella zoster virus, EpsteineBarr virus, cytomegalovirus, John Cunningham (JC) virus, Kaposi sarcoma-associated herpesvirus, and human papillomavirus in patients with ARDs. It also covered the effect of interferon-a, which is used to treat chronic hepatitis infection, and the induction of autoimmunity. © 2015 Elsevier Ltd. All rights reserved.

* Tel.: þ66 53 946839; fax: þ66 53 227203. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.berh.2015.05.010 1521-6942/© 2015 Elsevier Ltd. All rights reserved.

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Introduction During the past three decades, understanding of the immunopathogenesis of various autoimmune rheumatic diseases (ARDs) has been increasing. The use of immunosuppressive drugs (IMDs), both conventional immunosuppressive drugs (cIMDs) or conventional disease-modifying antirheumatic drugs (cDMARDs) and biologic agents or biologic disease modifying-antirheumatic drugs (bDMARDs), as well as newer treatment strategies (e.g. treat-to-target and combination therapy), results in not only better control of disease activity but also improved quality of life. However, such advantages of this treatment are not without cost. Treatment with corticosteroids and IMDs has been found to be associated with an increased risk of infections [1]. Furthermore, it is still not clear whether prolonged treatment with these compounds increases the risk of malignancies. Infection is common among developing countries, and patients with ARDs occasionally have underlying chronic infections. Furthermore, infection involving more than one organism is not uncommon. Many viruses can infect the body latently after primary infection. Thus, the major concern is whether to use IMDs, particularly bDMARDs, in such cases, as they may exacerbate or reactivate underlying latent virus infection and be detrimental to the host. This review focuses on the effects of IMDs on underlying chronic viral infections, particularly hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), varicella zoster virus (VZV), EpsteineBarr virus (EBV), cytomegalovirus (CMV), John Cunningham virus (JCV), Kaposi sarcomaassociated herpesvirus, and human papillomavirus (HPV). It also covers the effect of medications used in the treatment of these infections, particularly that of interferon-a (IFNa), and induction of autoimmunity.

Hepatitis B virus HBV is a double-stranded DNA (dsDNA) virus and belongs to the Hepadnaviridae family. It is one of the most common viral infections worldwide, and it is estimated to affect 400 million people. Its prevalence is low in the USA and northern Europe (<2%), but high in Southeast Asia, China, and Africa (>8%) [2,3]. Most patients acquire the virus during the perinatal period through vertical transmission, or during early childhood. Primary HBV infection usually is asymptomatic in 30e50% of cases in individuals older than 5 years. Although the virus is cleared in most patients (95%), resulting in lifelong immunity, 30e50% of those who acquire it during childhood develop chronic hepatitis B (CHB) infection [2]. After infection with HBV, active viral replication in the liver occurs, with a minimal host immune response (high serum HBV DNA levels, presence of HBeAg (HBeAgþ) and HBsAg (HBsAgþ), normal liver transaminase enzymes, and minimal hepatocyte changes), or the immune tolerance phase is observed. The second or immune clearance phase, which occurs in adolescents and adults, is characterized by a vigorous immune response to HBV, resulting in symptoms of clinical hepatitis with a marked increase in transaminase enzymes, together with hepatocyte necrosis and fibrosis. During this phase, HBV replication declines, and in 90% of cases, HBsAg and HBeAg gradually disappear or HBe seroconversion occurs (HBsAg/HBeAg). This stage is accompanied usually by the appearance of antibodies to HBV antigens (anti-HBsþ, anti-HBeþ, and anti-HBcþ). The third or low-replication phase is characterized by the presence of the abovementioned antibodies, and a very low or undetectable HBV DNA (<2000 IU/mL), normal transaminase enzymes, and minimal liver inflammation [2]. The presence of the anti-HBsþ state indicates full immunity from HBV infection (resolved HBV infection). However, some patients might still have a very low or undetectable level of anti-HBs antibodies (antiHBs/anti-HBcþ), and those with a very low level of HBV DNA (<2000 IU/mL) without evidence of liver inflammation are defined as having an “occult HBV infection.” Nevertheless, a certain percentage of “occult HBV-infected patients” have detectable HBV DNA, and they are at the risk of developing HBV reactivation (HBVr) [2]. Besides, CHB can be seen in up to 30% of HBeAg patients in this immuneinactive phase, which is due to HBV mutant strains that have lost their ability to secrete HBeAg, but can still replicate HBsAg. Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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Prevalence of HBV infection in patients with ARDs The prevalence of HBV infection in patients with ARDs was studied mainly in Asian countries, where its prevalence was similar to that among the general population (Table 1). However, a study from China in patients with ankylosing spondylitis found a significantly higher prevalence of HBsAgþ than rheumatoid arthritis (RA) and other rheumatic diseases, when compared with the general population [9]. Two other studies found a significantly lower prevalence of HBsAgþ among patients with autoimmune disease, when compared with those with non-autoimmune diseases [5], and similarly in patients with systemic lupus erythematosus (SLE) when compared with non-SLE patients or the general population [12]. HBV reactivation HBVr refers to the state of increased HBV DNA levels of >1 log10 when compared with the baseline value, or a change in the status of HBV DNA detection from negative to positive [16]. This Table 1 Prevalence of hepatitis B virus infection in patients with autoimmune rheumatic diseases (selected series). Authors, year, [Ref.] Country of study

Disease

No. of HBsAgþ patients (%)

Anti-HBcþ Anti-HBsþ p-Value (%) (%)

Watanabe et al., 2014 [4] Sui et al., 2014, [5]

RA SLE Autoimmune conditions (AIH, PBC, SLE, and UC) Non-autoimmune disease

7650 1031 938

1.1 0.4 2.24

25.2 13.7

3122

4.58

SLE

155

2.58

China

RA

223

Tan et al., 2012, [8] Zheng et al., 2012, [9]

China

General population (Liang et al., [7]) RA

476

11.2 (CHB1.7%) 8.7 (CHB 1.0%) 6.5 51.1

Chen et al., 2012, [10] Mori et al., 2011, [11] Zhao et al., 2010, [12]

Taiwan

439 606 172 698 200 175

23.92 12.87 14.53 9.60 8.18 10.28

239

0.8

China

SLE (hospitalization) 859 Non-SLE (hospitalization) 78,046 General population 20,000

2.33 12.75 9.57

Marcos et al., 2009, [13] Guennoc et al., 2009, [14] Permin et al., 1982, [15]

Spain

€gren's Primary Sjo syndrome Recent-onset arthritis

603

0.83

808

0.12

239

2.51

Zou, et at., 2013, [6]

Japan China

China

Japan

France

AS General population Other-SpA RA OA €gren's Primary Sjo syndrome RA

Denmark Autoimmune rheumatic diseases

16.7 10.1 p ¼ 0.0014 (autoimmune vs. non-autoimmune group) p ¼ 0.24 (SLE vs, non-autoimmune group) p ¼ NS

p < 0.05 (AS vs. other groups)

25.1 67.52 57.25 58.78

p < 0.01 (for HBsAg: SLE vs. general population). p < 0.001 (for HBsAg and anti-HBs: SLE vs. non-SLE)

11.71

AIH ¼ autoimmune hepatitis, AS ¼ ankylosing spondylitis, OA ¼ osteoarthritis, Other-SpA ¼ spondyloarthropathy other than ankylosing spondylitis, PBC ¼ primary biliary cirrhosis, RA ¼ rheumatoid arthritis, SLE ¼ systemic lupus erythematosus, UC ¼ ulcerative colitis.

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can occur in HBsAgþ or HBsAg/anti-HBcþ patients. The reactivation occurs as a result of lost host immune response (by either IMDs or acquired immune deficiency), and it causes unopposed HBV replication in the liver, resulting in increasing HBV DNA and expression of HBV-derived antigens. By discontinuing the immunosuppressive state and restoring the normal immune response, an immune reaction to the virus occurs, resulting in inflammation of the hepatocytes and liver. The clinical features of HBVr range from subclinical or asymptomatic to severe acute hepatitis, hepatic failure, and death. Several risk factors for reactivation have been identified. Although the male sex has been reported as a risk factor from a series of cancer patients [17], a recent review of HBVr in 138 patients with immune-mediated inflammatory disease (ARDs in 76.81%) found an equal distribution in both sexes [18]. HBsAgþ patients, and those with a high level of HBV DNA prior to immunosuppressive therapy, have a higher risk of HBVr when compared with those who are HBsAg/anti-HBcþ or have a lower HBV DNA level [18]. The risk of reactivation is lower in anti-HBsþ patients, as it indicates a full immune response to HBV infection. However, a very low level or loss of anti-HBs antibodies, during immunosuppressive therapy, might also increase the risk of reactivation [19]. The type of underlying disease is another risk factor for HBVr. The frequency of HBVr is high among patients with hematologic malignancies, particularly those with lymphomas (27.8%) [20], organ transplants (16.66%) [21], or chemotherapy for breast cancer (41.16%) [22]. This might be related to treating these conditions with high-dose corticosteroids and intense IMDs [23]. HBVr in patients with ARDs receiving antirheumatic therapy With newer strategies for treating ARDs, the combination therapy with corticosteroids and cIMDs or cDMARDs, with or without bDMARDs, is often used to control disease activity. Therefore, HBVr in patients with occult HBV infections or HBV carriers is not unexpected. However, information regarding the prevalence, clinical features, and outcome of HBVr among patients with ARDs is scarce, when compared with the data on malignancies or organ transplantation. Corticosteroids Corticosteroids are among the common anti-inflammatory drugs used in patients with ARDs, with a dosage that can range from low (<10 mg/day) to very high (pulse corticosteroids) for treating lifethreatening conditions. Corticosteroids have been shown to increase HBV transcription [24], and cases of HBVr after corticosteroid monotherapy for various conditions have been well described [25,26]. Reactivation usually occurs in patients undergoing continuous treatment at a moderate to high dose (20 mg/day) for >3 months [25]. Surprisingly, only sporadic cases of HBVr in patients with ARDs have been described, in which the incidence seems to be far less than the number of patients being treated with this agent alone. Further, the reactivation can be seen with low-dose corticosteroids (<10 mg/day of prednisolone) [27]. This might be partially due to most of these patients also receiving IMDs as part of the therapy [28]. Conventional immunosuppressive agents HBVr has been well recognized in patients receiving cIMDs or cDMARDs, and the risk is related to the intensity and use of combination cIMDs [23]. Similar to those using corticosteroids, reports of HBVr among patients with ARDs receiving IMD monotherapy are scarce, as the majority of them also received corticosteroids [28]. A recent prospective study found that the HBVr occurred in four of 211 (1.89%) patients with RA who were HBsAgþ or HBsAg/anti-HBcþ and received cDMARD therapy without antiviral prophylaxis. The reactivation occurred between 1 and 15 months post cDMARD administration [8]. A recent review found a prevalence of HBVr in 10 of 224 (4.46%) patients with rheumatic disease being treated with cDMARDs, eight of whom were given methotrexate (MTX) [28]. Another study of HBVr was performed in 288 patients with SLE receiving corticosteroids and cIMDs. Eight of them were HBsAgþ, and three had neither virology flares nor increased aminotransferase enzyme levels. An attempt to discontinue antiviral therapy (lamivudine) was made in three of five patients receiving it, and one of the three had a virological flare [29]. Patients who have HBVr can be managed with generally good outcomes. Despite cIMDs or cDMARDs being considered as low risk for Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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HBVr in patients with ARDs when used as monotherapy, acute fulminant hepatitis and fatal cases of HBVr with low-dose MTX have been described [30,31]. Biologic disease-modifying antirheumatic drugs During the past decade, the use of bDMARDs has been increasing, particularly in patients with RA, spondyloarthropathies, and SLE. These agents have been shown to control disease activity very effectively. Unfortunately, information on HBVr among patients with ARDs receiving bDMARDs, besides anti-TNFa, is limited. Anti-TNFa agents As TNFa plays an important role in both innate and adaptive immunity against HBV infection, blockade of TNFa can result in HBV replication and reactivation. The mechanisms by which anti-TNFa induces reactivation of the HBV virus include the activation of complement, antibody-dependent cellmedicated cytotoxicity, complement-dependent cytotoxicity, B-cell depletion, and T-cell-dependent humoral response [32]. Since approving anti-TNFa agents in the treatment of arthritic diseases, cases of HBVr occurring after their use have been reported (Table 2). However, the risk of HBVr in anti-TNFa monotherapy is difficult to determine, as a majority of the patients also receive corticosteroids and cIMDs or cDMARDs as part of the combination therapy. In a recent review of 620 patients with rheumatic disease treated with anti-TNFa (416 with past HBV infection and 204 with chronic HBV infection), antiviral prophylaxis was administered in 36 of those with chronic HBV infection. HBVr occurred in 59 cases (9.52%), of which 13 and 46 belonged to the past HBV infection and chronic HBV infection groups, respectively. The risk of reactivation was higher among patients with CHB and inactive HBV carriers than patients with occult HBV infection and those who did not receive antiviral prophylaxis. The outcome of the HBVr treated with antiviral therapy was considered good, as only one patient suffered from liver failure and died 26 months later [28]. Another recent meta-analysis, including 10 articles on HBVr in patients treated with anti-TNFa (nine with rheumatic diseases and one with psoriasis), found a pool estimate for the prevalence of HBVr at 4.2% (95% confidence interval (CI) 1.4e8.2), where the pool prevalence of HBVr was 3.0% and 15.4% among patients with occult HBV and overt HBV infection, respectively [40]. The prevalence of reactivation was slightly lower in patients who received etanercept (3.9%) than those receiving adalimumab (4.6%). The pool estimated prevalence of reactivation was 4% in those who did not receive antiviral prophylaxis [40]. The reason why patients treated with soluble receptor anti-TNFa have a lower risk of reactivation than those treated with monoclonal antibodies to anti-TNFa might be that the monoclonal antibody exhibits greater immunogenicity, and the frequency of administration at a certain interval results in a cytokine washout effect that does not occur in soluble receptor anti-TNFa [32]. Rituximab Currently, rituximab is indicated for rheumatoid arthritis, and antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis. Information regarding HBVr in patients with ARDs is far more limited than that of anti-TNFa. Experience with lymphomas clearly showed that HBVr was found more frequently in drug regimens containing rituximab than those without [23]. However, cases of patients receiving rituximab for HBVr in RA and ANCA-associated vasculitis have been reported rarely [41,42]. A recent prospective study of 14 HBV-infected patients with RA (HBsAgþ in two who received antiviral therapy, anti-HBsþ/anti-HBcþ in nine, and anti-HBs/anti-HBcþ in three) showed no HBVr during a follow-up period of 6e50 months (median 13 months) [43]. The low prevalence of HBVr from rituximab in patients with ARDs might be due to the aggressive screening for HBV infection and preemptive antiviral therapy among those who are at risk. Abatacept Information on the use of abatacept and HBVr is also limited. However, cases of HBVr treated with abatacept have been reported in RA patients with resolved and occulted HBV infection, and antiviral therapy successfully treated the HBVr [44]. In a retrospective study, eight RA patients with chronic HBV infection were treated with abatacept, and HBVr occurred in the four patients who did not receive antiviral prophylaxis, compared with no occurrence in the other four who did [45]. Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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Authors, year, [Ref.]

Country of report

Ye et al., 2014, [33]

China

No. of Disease patients

Anti-TNF treatment

HBV markers status

8/24 (33.3%) in HBsAgþ without prophylaxis; none in resolved HBV infection 49 (antiviral e 1/20 (5.0%) with prophylaxis ¼ 20) prophylaxis; 2/29 (7.7) without prophylaxis 18 (HBV DNAþ ¼ 18, 12 (HBV DNAþ ¼ 4, 58 (HBV DNA) 5/8 (62.5%) HBsAgþ antiviral prophylaxis ¼ 10) no prophylaxis) without prophylaxis; 1/4 (25%) antiHBs, HBV DNAþ without prophylaxis 2 (under cDMARDs with 60 e 2/60 (3.3%) of anti-HBcþ: antiviral prophylaxis) 1 MTX þ tacrolimus þ pred 2 MTX þ A þ pred 5 (HBV DNAþ in 3, antiviral 9 36 2/5 (40%) of HBsAgþ prophylaxis) without prophylaxis; 1/45 (2.2%) of anti-HBcþ, not under anti-TNF e 39 (HBV DNA-) 28 None

HBsAgþ

HBV reactivation Anti-HBcþ Anti-HBs

87

AS ¼ 4, PsA ¼ 3, RA ¼ 10

Not report

Ryu et al., 2012, [34] South Korea

49

AS ¼ 27, RA ¼ 22

A ¼ 6, E ¼ 38, I¼5

Lan et al., 2011, [35] Taiwan

88

RA

37 (chronic hepatitis B ¼ 6, antiviral prophylaxis ¼ 13)

Mori 2011, [11]

Japan

239

RA

A ¼ 2, E ¼ 18, I ¼ 19

Tamori et al., 2011, [36]

Japan

50

RA

Not reported

67

AS ¼ 4, PsA ¼ 4, RA ¼ 59 AS ¼ 32, PsA ¼ 21, RA ¼ 66, Others ¼ 12

A ¼ 19, E ¼ 23, I ¼ 25 (A ¼ 62, E ¼ 64, 14 (chronic hepatitis B ¼ 3, I ¼ 43)* antiviral prophylaxis ¼ 14)

AS ¼ 59, JRA ¼ 2, PsA ¼ 1, RA ¼ 41

Not reported

Caporali et al., 2010, Italy [37] Vassilopoulos et al., Greece 2010, [38]

Chung et al., 2009, [39]

131

South Korea 103

8 (carriers)

Anti-HBsþ

50

9

e

10

1 chronic hepatitis B (with lamivudine resistant mutant); None in resolved HBV infection 1/8 (12.5%)

AS ¼ ankylosing spondylitis, JRA ¼ juvenile rheumatoid arthritis, PsA ¼ psoriatic arthritis, RA ¼ rheumatoid arthritis, A ¼ adalimumab, cDMARDs ¼ conventional disease-modifying antirheumatic drugs, E ¼ etanercept, I ¼ infliximab, pred ¼ prednisone, * ¼ some patients were treated with two or three agents, and the cumulative number exceeded 131.

W. Louthrenoo / Best Practice & Research Clinical Rheumatology xxx (2015) 1e24

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Table 2 Hepatitis B virus (HBV) reactivation with anti-TNFa therapy in patients with rheumatic disease with chronic or past HBV infection (selected series).

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Tocilizumab So far, three reports have addressed the use of tocilizumab in patients with HBV infection. The first was a patient with RA who was HBsAgþ with a high viral load, and who did not receive antiviral prophylaxis [46]. The second was a patient with active RA who previously had HBVr with infliximab, but the virus was controlled successfully (undetectable HBV DNA) by antiviral therapy [47]. The third was a patient with adult-onset Still's disease who had active HBV infection (HBsAgþ with high viral load) together with antiviral prophylaxis [48]. None of these patients developed HBVr. Tofacitinib and belimumab are two recent IMDs approved for the treatment of RA and SLE, respectively. However, no case of HBVr from these two compounds has been reported at the time of this review.

Management and monitoring of HBV-infected patients requiring immunosuppressive therapy It is clear that patients with CHB, HBsAgþ, and past HBV infection, as well as active viral replication (high HBV DNA), are at a risk of HBVr after corticosteroids or immunosuppressive therapy; therefore, all patients with ARDs starting IMDs (either cIMDs or cDMARDs, or bDMARDs) should be screened for HBV infection (HBsAg, anti-HBs, and anti-HBc) [49,50]. HBV vaccination should be given to nonexposed patients (HBsAg/anti-HBs/anti-HBc). Those who have been vaccinated and are already immune to HBV (anti-HBsþ/anti-HBc) need not take further action. However, those with current HBV infection (CHB, HBsAgþ as a carrier, or past HBV infection (anti-HBcþ/anti-HBs or anti-HBsþ)) should consult a hepatologist for a treatment plan and monitoring. HBsAgþ patients should receive preemptive antiviral therapy. It is less clear how anti-HBcþ patients, with or without anti-HBs antibodies, are managed. In general, anti-HBcþ/anti-HBsþ patients are considered immune to HBV infection, and their risk of HBVr is minimal if they are receiving cDMARDs. However, a significant decrease in anti-HBsAb titer, of up to 70% of the baseline value, but not below 10 IU/L, has been observed in many cases of anti-TNFa therapy [35,36,38,51]. This finding should be of concern among patients with a very low anti-HBsAb level, as it might become negative. The risk of HBVr in resolved HBV infection, with negative HBV DNA (<2000 U/mL), is lower than that with high HBV DNA (or occult infection); therefore, HBV DNApositive patients should start preemptive antiviral therapy promptly before commencing IMDs. For those with HBV DNA at <2000 IU/mL, careful monitoring of the aspartate transaminase (AST), alanine transaminase (ALT), and HBV DNA level is recommended during IMD therapy, and antiviral therapy should be started as soon as the HBV DNA level increases. A marked increase in the serum HBV DNA level usually occurs prior to the elevation of the ALT with a median duration of 18.5 weeks (range, 12e28) [52]. In countries where HBV DNA testing is costly or not widely available, preemptive therapy with antiviral therapy might be an option. Antiviral therapy should be given during IMD therapy and for at least 6e12 months after cessation, with careful monitoring of AST, ALT, HBeAg, HBeAb, and HBV DNA level (in those who were HBsAgþ), and AST, ALT and HBV DNA level (in those with resolved HBV infection) [16,53]. The currently approved antiviral medications for HBV infection are conventional IFNa, pegylated-IFNa, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. The choice of antiviral therapy depends on the duration and intensity of the IMDs used, and the availability of antiviral drugs in each country, as well as the prevalence of resistant strains of the virus (e.g., lamivudine-resistant strain). Elevation of AST or ALT levels during IMD therapy in HBV-infected patients is not always a case of HBVr. Differential diagnosis should also include drug-induced liver disease, hepatic involvement in rheumatic disease, alcoholic and nonalcoholic hepatitis, autoimmune hepatitis, thyroid disease, and other infectious causes of hepatitis (e.g., EBV, HIV, CMV, etc.). Hepatitis C virus HCV is a single-stranded ribonucleic acid (RNA) virus of the Flaviviridae family. It is estimated that 3% of the world's population is infected by this virus. The prevalence of HCV infection ranges from 1.6% in the USA [54], and 1e5% in Asia [3], to as high as 14.7% in Egypt [55]. The prevalence is higher among high-risk groups (e.g., prisoners and intravenous drug users (IVDUs)). Parenteral exposure, particularly Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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in IVDUs, is the primary source of HCV acquisition. Currently, HCV is the major cause of chronic hepatitis globally. The natural course of HCV infection is complex [56]. After acute infection, HCV can be cleared in 20% of patients spontaneously, but 55e85% progress to chronic disease in which 5e25% develop cirrhosis after being infected for 25e30 years. Antibodies to HCV can be detected 8e10 weeks after infection. Male sex, alcohol intake, older age at infection, obesity, and coinfection with HBV or HIV are factors associated with progression. Among those who develop cirrhosis, the risk of developing hepatocellular carcinoma is approximately 1e4%/year. Prevalence of HCV infection in patients with ARDs The prevalence of HCV infection varies among patients with ARDs, but it is similar to that of the general population (Table 3). It is low in the USA and western Europe, and high in Egypt in particular. Interestingly, many studies found that the prevalence of HCV infection was higher in patients with SLE than in the general population or controls. A high prevalence in patients with SLE was also observed in ethnic African Americans in the USA. Rheumatic manifestations of HCV infection Various immune and rheumatic manifestations, as a complication of HCV infection, have been well recognized and reviewed [69]. Patients with HCV infection have a strong association with type

Table 3 Prevalence of hepatitis C virus infection in patients with autoimmune rheumatic diseases (selected series). Authors, year, [Ref.]

Country of study

Disease

No. of patients

HCVþ (%)

Ansemant et al., 2012, [57] El Garf et al., 2012, [58]

France

Recent-onset arthritis

233

0

Egypt

patients with rheumatic disease (hospitalization)

157

SLE RA Early-onset arthritis SLE Control €gren's syndrome Primary Sjo SLE (African American 85%) Blood donor SLE RA Others (CTD and SpA) PsA DJD RA RA, age > 60 years RA SLE Blood donor APS

75 17 808 50 10,343 305 40 20,816 175 89 103 100 100 100 196 (from 4769 data base) 309 134 200 88

29 (18.5%) * HCV-RNA (performed in 72.4%) 5 (6.7) 3 (17.6) 7 (0.96%) 3 (6.0) 44 (0.42) 9 (2.95) 4 (10.0) 92 (0.44) 4 (2.3) 3 (3.4) 0 1 (1.0%) 4 (4.0%) 0 1 (0.51)

Blood donor

200

Guennoc et al., 2009, [14] Mohan et al., 2009, [59]

France India

Ceribelli et al., 2008, [60] Ahmed et al., 2006, [61]

Italy USA

Barbosa et al., 2005, [62]

Brazil

Palazzi et al., 2005, [63]

Italy

Csepregi et al., 2004, [64] Hsu et al., 2003, [65]

Hungary USA*

Maillefert et al., 2002, [66] Ramos-Casals et al., 2000, [67] Munoz-Rodriguez et al., 1999, [68]

France Spain Spain

1 (0.32) 15 (11.2%) 2 (1.0) 2 (2.27) HCV-RNA negative 2 (1.0%)

p-Value

p ¼ 0.001

p < 0.0001

p ¼ 0.68

p < 0.01 p ¼ 0.6

APS ¼ antiphospholipid syndrome, CTD ¼ connective tissue diseases, DJD ¼ degenerative disc disease, PsA ¼ psoriatic arthritis, RA ¼ rheumatoid arthritis, SLE ¼ systemic lupus erythematosus, SpA ¼ spondyloarthropathy, * ¼ The National Health and Nutrition Examination Survey.

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II and III cryoglobulinemia, and they can show various manifestations ranging from cutaneous vasculitis, peripheral neuropathy to glomerulonephritis. In addition, a variety of autoantibodies including antinuclear antibodies (ANAs), anti-smooth muscle antibodies, rheumatoid factors (RF), ANCA, antibodies to C-reactive protein, antibodies to C1q, and antibodies to endothelial cells have € gren's syndrome is also a common manibeen identified in the sera of HCV-infected patients. Sjo €gren's syndrome, the low frequency of ANAs, festation. Although clinically similar to primary Sjo anti-Ro, and anti-La antibodies; low complement level; and the presence of cryoglobulin and €gren's syndrome. Chronic polyarthritis is the monoclonal gammopathy favor HCV-associated Sjo most common arthritis pattern associated with HCV infection. It often features non-erosion involving the small joints of the hands, thus mimicking RA. Indeed, it is not uncommon to observe a patient with coexisting RA and HCV infection. Therefore, it is sometimes difficult to distinguish coexisting RA and HCV infection from chronic HCV arthropathies. In contrast to the RF, which can be seen but does not correlate with the activity of arthritis in HCV arthropathy, anti-CCP antibodies are usually negative in HCV-associated arthropathy, thus helping to distinguish it from RA [70]. HCV reactivation in patients with rheumatic disease receiving antirheumatic therapy The definition and mechanism for HCVr are similar to that of HBVr. Cases of HCVr occurring in cancer patients receiving IMDs and biologic agents have been well described and reviewed [71], but reported cases in those with ARDs seem to be less common. Information on HCVr in patients with ARDs receiving corticosteroids, cIMDs, or cDMARDs is very limited. MTX and leflunomide are of particular concern when administered to HCV-infected patients, and they should not be used due to their possible hepatotoxic effect on the liver [49,72]. Cyclosporine A, which has an inhibitory effect on HCV replication, has been used successfully in various ARDs, without HCVr or deterioration of liver functions [73]. A recent systematic review reported 153 HCV-infected patients, who had various rheumatic diseases and other inflammatory conditions, and were treated with anti-TNFa agents; only one definite case of HCVr with worsening hepatic function and five suspected cases (elevation of transaminases not associated with increased HCV viral load and vice versa) were identified [74]. A majority of these patients received etanercept as an anti-TNFa agent, and the American College of Rheumatology (ACR) recommends its use as preferable for RA patients with HCV infection [75]. A recent multicenter study of 15 patients with psoriatic arthritis, and HCV infection treated with antiTNFa, also showed no HCVr [76]. Although rituximab can be used successfully in most cases of cryoglobulinemic vasculitis associated with HCV infection, without causing HCVr or deterioration of liver functions [77], a case of HCVr after rituximab therapy in RA was described recently [78]. Tocilizumab was found to be safe for use in RA patients with HCV infection, without changes in viral load or liver functions [79,80]. Management and monitoring of HCV-infected patients requiring immunosuppressive therapy Similar to those with HBV infection, all patients with ARDs requiring IMD therapy should be screened for HCV infection [49,50]. A hepatologist should be consulted if the anti-HCV becomes positive (anti-HCVþ), and HCV RNA should be determined and followed up. These patients should be evaluated further for the severity of underlying chronic HCV infection in advanced fibrosis or cirrhosis by laboratory, imaging, or histopathological studies, which would help the hepatologist to decide whether or not antiviral therapy is needed. Although the use of IMDs in ARD patients with HCV infection seems to be safe, it is contraindicated in those who have decompensated liver disease (Child B or C), due to the risk of potentially severe infection. Treatment of HCV infection is being reviewed currently, and the combination of IFNa or pegylated-IFNa and ribavirin is the standard of care for most patients at present [56,81]. However, the possibility of IFNa-induced immunologic disorders in patients with rheumatic diseases is of concern. Simeprevir, sofosbuvir, and ribavirin have been approved for the treatment of chronic HCV infection. The IFNa-free regimens for treating chronic hepatitis C (CHC) infection are underresearched. Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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IFNa therapy and the induction of autoimmunity in patients with ARDs IFNs are a family of cytokines that play a central role in the regulation of the antiviral property and antiproliferative responses of the immune system. They can be classified into three main types: type I, type II, and type III IFNs. The role played by type I IFN in the induction and maintenance of autoimmunity has been studied and reviewed [82,83]. In brief, upon stimulation of the Toll-like receptors (TLRs) on plasmacytoid dendritic cells (pDCs) and dendritic cells (DCs) by endogenous or exogenous stimuli, type I IFN (IFNa and IFNb) is produced, which activates DCs in turn leading to the expression of MHC class I and co-stimulatory molecules, and the activation of T cells. In addition, stimulation of B cells by type I IFN promotes B-cell differentiation into plasma cells and production of autoantibodies. These autoantibodies and/or immune complexes bind to the cell surface and cause systemic autoimmune diseases. In addition to use in the treatment of CHB and CHC, type I IFN, particularly IFNa, has been used in other autoimmune diseases, such as Behcet's disease, ChurgeStrauss syndrome, and polyarteritis nodosa [84]. As type I IFN can stimulate the autoimmune reaction, its use in ARDs and the possibility of aggravating or worsening ARD conditions are of particular concern. A wide range of autoimmune phenomena and autoimmune diseases have been reported during IFNa therapy, mostly for chronic HCV infection. However, interpretation of the results should be cautionary, as many autoimmune phenomena have been reported in association with this virus infection [69]. In a large cohort study of 677 patients with CHC infection treated with IFNa, ANA, anti-dsDNA, anti-thyroglobulin, and antimicrosomal antibodies were found in 13.6%, 15.5%, 1.2%, and 3.2% of patients, respectively. At the end of treatment, elevation of ANA and anti-dsDNA was identified in 39.1% and 27.6% of patients, respectively [85]. Thyroid disorders and diabetes mellitus were common and seen in 18 (2.66%) and five (0.73%) patients, respectively. Six patients developed autoimmune disorders, two of whom developed RA (0.29%), two autoimmune hepatitis (0.29%), one SLE (0.15%), and one autoimmune thrombocytopenia (0.15%). These autoimmune diseases occurred between 5 and 24 weeks of treatment. In a recent review [86], thyroid disease was the most common organ-specific autoimmunity associated with IFNa treatment, with an incidence of antithyroid antibodies of 1.9e40.0%. The majority of these patients were asymptomatic, but symptomatic disease was found in 0.6e7.0%. Type I diabetes mellitus and ARDs (e.g., SLE, RA, etc.) were found in <1.0%. Studies focusing on the rheumatologic complications of IFNa are scarce. The clinical features of IFNa-induced SLE are different from those of other drug-induced SLE, in that the mucocutaneous and renal involvement is more common, and anti-dsDNA can be seen in up to 50% of the patients. Arthralgia/arthritis is common, and serositis can be seen in up to 20% of cases. Most cases have hightiter ANAs. The disease can present from 2 weeks to 7 years after IFNa therapy, but it usually resolves after cessation of IFNa treatment [87]. Neonatal lupus following maternal treatment with IFNa has also been reported [88]. IFNa-induced RA or polyarthritis is rare. The arthritis occurs a few weeks to 10 months after IFNa therapy. Symmetric polyarthritis, usually involving small joints of the hands, is common and seen in 63% of cases. ANA, RF, and anti-CCP can be seen in 72%, 34%, and 30% of cases, respectively [89,90]. The presence of anti-CCP and erosive changes makes IFN-induced polyarthritis or RA different from HCV-associated arthritis. Cessation of INFa, with and without cDMARDs, results in remission in 89% and 71% of cases, respectively, and patients with HLA-DR4 tend to have persistent arthritis. The arthritis recurs after restarting IFNa in 63% of cases [89]. IFNa-induced sarcoidosis has been well described, with an incidence of 5% [86]. The time between IFNa therapy and diagnosis of sarcoidosis ranges from 2 to 168 weeks (mean 34 weeks). The lung is involved in approximately 70% of cases. However, involvement of the skin, particularly subcutaneous nodules, is much more common in IFNa-induced sarcoidosis than idiopathic sarcoidosis (60% vs. 25%), whereas erythema nodosum is observed less frequently in IFNa-induced sarcoidosis [91]. Other ARDs are a complication of IFNa therapy, and they include dermatomyositis/polymyositis, SLE, RA, mixed €gren's syndrome, and various autoantibodies [92]. connective tissue disease, Sjo Although many ARDs have been described in association with IFNa therapy, they are uncommon, and the syndrome usually resolves after IFNa treatment is discontinued. Therefore, these complications should not preclude the use of IFNa in the treatment of CHB and CHC infection. However, careful monitoring for possible ARD development during IFNa treatment is needed. Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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Human immunodeficiency virus HIV is a retrovirus of the Retroviridae family. The virus infects and destroys the immune cells of the body causing acquired immunodeficiency syndrome (AIDS), thus creating a major health problem. HIV infection is a worldwide epidemic, with the highest prevalence (15e28%) in sub-Saharan Africa, eastern Europe, and the Caribbean. In 2011, the Joint United Nations Program on HIV/AIDS (UNAIDS) estimated that 34.2 million people were living with HIV infection [93]. The musculoskeletal system is among the common manifestations of HIV infection. Various rheumatologic diseases associated with HIV infection have been well described and reviewed [94]. These rheumatic diseases can be classified as follows: (A) disorder directly associated with HIV infection (articular syndromes (e.g., spondyloarthropathies, AIDS-associated arthralgia/arthritis, etc.), AIDS-associated muscle disorders (e.g., poly/ dermatomyositis, fibromyalgia, noninflammatory necrotizing myopathy, etc.), diffuse infiltrative lymphocytosis syndrome, vasculitides, and lupus-like syndrome); (B) disorders as a consequence of immunodeficiency, for example, septic arthritis, osteomyelitis, etc.; and (C) disorder as a result of HIV treatment, for example, gout, rhabdomyolysis, parotid lipomatosis, etc. The rheumatic syndromes directly associated with HIV infection share many clinical features similar to those with non-HIV infection, but the former rheumatic arthritis tends to be more severe and resistant to conventional treatment. Many patients are unaware of their HIV infection when they present with rheumatic symptoms [95]. The paradoxical activity between HIV infection and RA and SLE has been well recognized. The CD4þ T cells play a critical role in the development of RA and SLE. In advanced HIV infection, there is decreased TNF, interleukin-1 (IL-1), and IFNg production, with increased IL-4 and IL-10 production, which can diminish the activity of RA and SLE. Treatment with highly active antiretroviral therapy (HAART) results in a diminishing number of HIV viruses and increasing number of CD4þ T cells, thus restoring the immune system and exacerbating RA and SLE [96,97]. Conversely, the use of IMDs can lead to the exacerbation of underlying HIV infection [97]. Effects of immunosuppressive therapy on rheumatic diseases in HIV-infected patients Prior to the era of HAART, treatment of inflammatory arthritis associated with HIV infection was problematic, as the use of IMDs or phototherapy in these patients led to the development of full-blown AIDS, and it was considered contraindicated [98,99]. Etretinate and sulfasalazine can be used without a detrimental effect on the immune status [100,101]. Hydroxychloroquine can be used as it has been shown to inhibit HIV replication [102]. With the development of HAART and strategies in treating HIV infection, treatment of these conditions has been more successful. MTX and anti-TNFa has been used successfully in HIV-infected patients with rheumatic diseases, providing underlying HIV infection is controlled and the patient is not severely immunocompromised (CD4 count of >200/mm3 and HIV viral load of <60,000 copies/mm3) [103]. Rituximab has been used successfully in an HIV-infected patient with ANCA-associated vasculitis, without deterioration of the HIV immune status [104]. Interestingly, a recent in vitro study showed that tofacitinib can inhibit HIV replication and reactivation; however, the possible use of this compound in treating inflammatory arthritis in HIV-infected patients needs to be determined [105]. Changes in the spectrum of rheumatic diseases after the HAART era The institution of HAART has made significant changes in the natural history, long-term outcomes, morbidity, and mortality of HIV-infected patients. A longitudinal study from Cleveland showed a decline in the incidence of spondyloarthropathies and connective tissue diseases [106], whereas an increase in the incidence of septic and malignant complications was reported from New Orleans [107]. A decline in the incidence of DILS has been reported from Houston [108], but not from Italy [109]. Thus, the changing pattern of rheumatic manifestations in the HAART era needs to be investigated further. In addition, a spectrum of autoimmune or autoinflammatory syndrome, presenting as a part of the immune reconstitution inflammatory syndrome (IRIS), has been reported among patients receiving HAART. These diseases occur as a result of increasing number of CD4þ T cells and memory T cells after Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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HAART, resulting in activation of the immune system after quiescence from a previously immunosuppressive state of advanced HIV infection [106]. In a recent report from France of 52 patients with autoimmune diseases associated with HIV infection, 24 (65.3%) of them developed autoimmune disease after HIV infection, but unfortunately the association between autoimmune disease and HAART was not provided [110]. In another report from Taiwan, 26 cases of HIV-associated autoimmune diseases were identified, in which 15 (57.9%) developed arthritis after HAART, with a duration range from 1 to 144 months [111]. The spectrum of autoimmune diseases ranges through RA, AS, SLE, anti€gren's syndrome to primary biliary cirrhosis phospholipid syndrome, vasculitis, thyroid disease, Sjo [110,111]. The treatment of HIV-associated autoimmune syndrome, as a part of IRIS, is similar to that in patients without HIV infection, and the use of IMDs should be cautionary. The treatment outcome of these autoimmune syndromes is generally favorable [110,111].

Varicella zoster virus VZV is an a-herpesvirus of the Varicellovirus genus, which causes varicella (or chicken pox) and zoster (or shingles). Primary infection occurs in the epithelial cell mucosa of the upper respiratory tract. The virus infects T cells, and it is transported to the skin via the bloodstream. During primary infection, the virus gains access to the sensory nerve ganglia by retrograde axonal transport from the skin, causing latent infection. Recovery from varicella is associated with VZV-specific T-cell-mediated immunity (T-CMI) shortly after the disappearance of rashes. In a situation where T-CMI is impaired, reactivation of VZV occurs, in which the virus reaches the skin via anterogate axonal transport, causing symptoms of zoster, which are determined by the dermatome innervated by the affected ganglion. The median incidence of zoster infection worldwide is approximately 4e4.5/1000 person-years, which is increasing, particularly in patients aged over 50 years [112]. The incidence of herpes zoster is increasing in various rheumatic diseases when compared with the general population (Table 4). The highest incidence is seen among patients with Wegener's granulomatosis and SLE. The incidence of herpes zoster in RA is higher than that in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) [120], and it has been increasing since 1990 [114]. The variation in incidence might be related to the population studied and underlying diseases as well as the use of IMDs in these patients.

Table 4 Incidence of herpes zoster among patients with autoimmune rheumatic diseases (selected series). Authors, year, [Ref.]

Source of data

Chakravarty et al., 2013, [113]

National data bank for rheumatic diseases, USA

Patient studied

SLE Noninflammatory MSK Veetil et al., 2013, [114] Rochester Epidemiology RA Project, USA Non-RA Borba et al., 2010, [115] Lupus Clinic Database, Brazil SLE Smitten et al., 2007, [116] PharMetrics claims RA database, USA Non-RA UK General Practice RA Research Database, UK Non-RA Wolfe et al., 2006, [117] National data bank for RA rheumatic diseases, USA Noninflammatory MSK Wung et al., 2005, [118] Wegener's Granulomatosis Wegener's Etanercept Trial (WGET) granulomatosis Park et al., 2004, [119] Korea SLE RA

N

Incidence rate, HR (95% CI) per 1000 patient-year

1845 2775

12.0 8.7

1.7 (1.08e2.71)

813 813 1145 122,272 1,000,000 38,621 500,000 10,614 1721

12.1 5.4 6.4 9.83 3.71 10.6 4.1 13.2 14.6

2.4 (1.7e3.5)

180

45.0

303 1748

32.5 3.9

1.91 (1.80e2.03) 1.65 (1.57e1.75) 1.0 (0.7e1.3)

(27e70)

MSK ¼ musculoskeletal symptoms, RA ¼ rheumatoid arthritis, SLE ¼ systemic lupus erythematosus, HR ¼ hazard ratio, 95% CI ¼ 95% confidence interval.

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VZV reactivation in ARD patients receiving antirheumatic therapy Despite a high incidence of herpes zoster developing among patients with ARDs, the effect of IMD therapy, reactivation of VZV (VZVr), and development of herpes zoster has not been studied extensively. Studies on the effect of IMD therapy and development of herpes zoster in patients with ARDs showed conflicting results. A cohort study from the British Society of Rheumatology (BSR) found that the risk of herpes zoster in RA among anti-TNFa users was significantly higher than in cDMARDs users (1.6/100 patient-years vs. 0.8/100 patient-years, hazard ratio (HR) 1.7) [121]. The HR among infliximab, etanercept, and adalimumab users when compared with cDMARD users was 2.2, 1.7, and 1.5, respectively. By contrast, another large study in the USA found no difference in the incidence of herpes zoster between anti-TNFa and cDMARD users [120], and the incidence was comparable among the three types of anti-TNFa (infliximab, etanercept, and adalimumab). The use of corticosteroids (10 mg/day of prednisone) with IMDs was associated with an increased risk of herpes zoster (HR: 1.69e2.13) when compared with those who did not use corticosteroids [120,122]. A recent systematic review and metaanalysis found a relative risk (RR) of a herpes zoster episode to be 1.61 (95% CI 1.16e2.23) among antiTNFa users when compared with cDMARD users, and the risk was highest in infliximab use, followed by etanercept and adalimumab, consecutively [123]. A large study of patients with RA in the USA found that herpes zoster development was associated with the use of IMDs, for example, cyclophosphamide (HR 4.2), azathioprine (HR 2.0), prednisone (HR 1.5), and leflunomide (HR 1.4), whereas MTX was not associated with an increased risk of herpes zoster [117]. A recent systematic review confirmed that there was no increased risk of herpes zoster among patients with RA treated with MTX [124]. A study using the Medicare claim data found that the incidence rate (per 100 patient-years) of herpes zoster in patients with RA was 1.87, 2.27, and 2.15 among abatacept, rituximab, and tocilizumab users, respectively, and it was no different from that in anti-TNFa users (1.61e2.45 per 100 patient-years). In addition, African Americans were less likely to develop herpes zoster than Caucasians (HR: 0.59, 95% CI: 0.38e0.91), whereas Asians and Hispanics had a similar risk (HR: 1.20, 95% CI: 0.63e2.25 and HR: 0.79, 95% CI: 0.56e1.11, respectively) [125]. However, a study on the long-term safety over 9.5 years of rituximab use in patients with RA in clinical trial programs (11,962 patient-years) showed the rate of herpes zoster to be 9.0/1000 patient-years, which did not differ from the general population [126]. A case of acute encephalomyelitis from reactivation of multiple herpesviruses, such as VZV, EBV, and CMV, after abatacept treatment, has been reported [127]. Notably, the risk of herpes zoster among tofacitinib users (from the tofacitinib development program) was high, with an incidence rate of 4.4/ 100 patient-years (95% CI 6.4e9.3) [128]. In a study of patients with SLE, the development of herpes zoster was associated with the use of cyclophosphamide and MTX, but not azathioprine [119]. This finding was different from a recent report of a large number of patients with SLE, in which herpes zoster was found to be associated with the use of corticosteroids during the past 6 months, and the use of mycophenolate mofetil, but not cyclophosphamide [113]. A large study of herpes zoster in SLE found that it often occurred during the late course of lupus disease (>5 years), and it was associated usually with mild to moderate disease activity (SLEDAI score < 8) [115]. By contrast, a report from Japan found that herpes zoster occurred during the first year of lupus onset in >50% of cases [129]. Female sex and impaired renal function were found to be risk factors for the development of herpes zoster in patients with Wegener's granulomatosis [118]. The clinical features of herpes zoster in immunocompromised patients are similar to those in healthy individuals, but patients associated with bDMARDs tend to have more severe disease, with multi-dermatome lesions than those associated with cDMARDs [123]. Acyclovir, famciclovir, and valacyclovir can be used as they have been approved by the Food and Drug Administration (FDA) [130]. EpsteineBarr virus EBV is a DNA virus of the herpes family (human herpesvirus 4: HHV-4). It is a ubiquitous infectious agent that latently infects approximately 95% of the world's population. Primary infection usually occurs during childhood and adolescence, causing asymptomatic infection or infectious mononucleosis in 30e70% of cases. The virus initially infects epithelial cells in the oropharynx and nasopharynx, then enters the underlying tissue, and infects B cells before persisting in resting memory B cells for the rest Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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of the individual's life. The viral DNA is replicated using the host cell DNA polymerase, together with the host's chromosomal DNA [131]. Several studies have shown the link between EBV infection and systemic autoimmune diseases, €gren's syndrome [131]. Increased EBV viral load has been demonstrated in particularly RA, SLE, and Sjo the peripheral blood of these patients, indicating impaired T-CMI in the control of EBV infection. EBV, IMDs, and the development of lymphoma in patients with rheumatic disease EBV has been associated with lymphoproliferative disorders (LPDs), particularly lymphoma; however, the association between EBV and lymphoma in patients with ARDs is unclear. Cases of EBVassociated lymphoma in patients with RA receiving IMDs (particularly MTX) have been reported and reviewed [132]. A majority of them were noneHodgkin's lymphoma (diffuse large B-cell type). The EBV has been observed in 30e60% of these patients. Spontaneous complete remission was observed in 23e76% of cases, and it usually occurred within 4 weeks from cessation of immunosuppressive therapy. The prognosis of LPD associated with RA was unfavorable when compared with sporadic cases. Immunodeficiency caused by the use of MTX and IMDs, resulting in decreased cytotoxic T-cell surveillance against EBV-infected B cells as well as reactivating latent EBV, might be the mechanism that develops lymphoma in these patients [133]. A large caseecontrol study of 378 Swedish long-standing RA patients with malignant lymphoma (EBV was present in 12% of the cases) found that the lymphoma was associated with high disease activity and poor functional class. Although previous treatment with cDMARDs did not increase the risk of lymphoma as a whole, a subanalysis showed that azathioprine did so in patients who had never used it (odds ratio (OR): 4.3, 95% CI 1.6e12.0) [134]. Another report from the same Swedish group identified 505 hematologic malignancies among 60,930 patients with RA. They found that the risk of leukemia and lymphoma was increased in RA, but not of multiple myeloma (standardize incidence ratio (SIR) approximately 2). The SIR was higher (2.9) among antiTNFa users. However, the lymphoma risk disappeared after adjustment for age, sex, and duration of RA [135]. A recent meta-analysis covering 63 randomized control trials of bDMARDs in RA (including abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab) found no significantly increased risk of any specific cancer. The OR for lymphoma was 2.1 (95% CI, 0.55e8.4) in patients receiving anti-TNFa, which did not reach statistical significance [136]. EBV reactivation in patients with ARDs receiving antirheumatic therapy Studies on EBV reactivation (EBVr), with the use of IMDs, have shown conflicting results. An in vitro study showed that MTX could activate the release of EBV from latently infected cell lines, and patients treated with MTX had significantly higher EBV viral load than those who received other cDMARDs [133]. By contrast, another study could not demonstrate increased EBV viral load or EBVr after shortterm treatment (3 months) with IMDs (MTX or anti-TNFa) in patients with rheumatic diseases [137]. However, cases of EBVr with hemophagocytic syndrome after the use of cDMARDs or bDMARDs have been described [127,138]. Whether a longer duration of immunosuppression is needed for the development of EBVr is not clear. Cytomegalovirus CMV or human herpesvirus-5 (HHV-5) is a highly specific human infection. The seroprevalence of the infection rate in the general population varies from 70% to 100%. The prevalence is low in Europe and the USA, but higher in developing countries, particularly Africa and Southeast Asia, and it increases with age. The virus is not highly contagious, and transmission occurs by direct or indirect contact with blood, urine, vaginal secretion, semen, and milk. After primary infection, which is usually mild or asymptomatic, the virus can remain latent in multiple sites of the body, and it can be reactivated in the presence of acute stressful conditions or immune activation. Studies have shown that CMV can modulate the immune system; however, whether it is the cause of autoimmune diseases is still not clear. Most reported cases of CMV infections occur in patients receiving IMDs for organ transplants, malignancies, etc. or HIV infection [139]. Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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Despite the extensive use of corticosteroids and IMDs in patients with ARDs, reported cases of CMVinfected patients, some of which might also represent CMV reactivation (CMVr), are limited. This might be due in part to underreporting or failed recognition of this condition. However, attention to this has been increasing recently, as the method for detection is more accessible and reliable. A questionnairebased study in Japan covered 7377 patients with ARDs, and CMV infection was identified in 151 (2.0%), with a mortality rate of 31.7% [140]. In a study of 35 patients with connective tissue disease receiving corticosteroids only (prednisolone at 0.5 mg/kg/day), CMV-pp65 antigenemia, which indicates active CMV infection, was identified in 40%. Symptomatic CMV infection (pneumonitis and encephalitis) was found in 8.6% of the patients [141]. The prevalence of symptomatic CMV infection is up to 50% among patients receiving higher-dose corticosteroids and IMDs, particularly intravenous cyclophosphamide [142]. In a study of 88 SLE patients with acute viral infection, 48.8% were found to be infected with CMV, the most common organism identified, which contributed to death in 41.7% [143]. A recent study of 105 CMV-infected patients with SLE found that the virus contributes to a new onset of SLE, which exacerbates SLE and CMV infection by mimicking SLE flares in approximately each of one-third of cases. Hemocytopenia, fever, and liver dysfunction were the most common manifestations seen in 54e81% of the cases. Ganciclovir treatment led to a negative CMV-DNA viral load in all of the patients, but CMVIgM and CMV-pp65 were still positive in almost half of them. Relapse of CMV infection or CMVr occurred in approximately 40% of these cases within 3 months after cessation of ganciclovir. This indicates that 14e21 days of ganciclovir therapy might be inadequate, and monitoring CMV-pp65 should be used as a marker for discontinuing the treatment [144]. CMVr in patients with ARDs treated with bDMARDs is of particular concern, although no CMVr was identified in a short-term study of 15 patients with RA treated with infliximab [145]. However, cases of CMV infection were identified in patients with RA and juvenile RA being treated with anti-TNFa [146]. CMVr or infection has also been reported in patients with ARDs being treated with other bDMARDs [127,147]. Therefore, more cases of CMV infection and CMVr can be expected in the future. The clinical symptoms of CMV infection or CMVr usually involve multiple organ systems, including fever, hemocytopenia, cough, abdominal pain, diarrhea, etc., which might be confused with exacerbation of underlying ARDs or the presence of other infections [140]. The majority of CMVr cases can be controlled by ganciclovir or valganciclovir. John Cunningham virus JCV is a double-stranded, circular DNA virus of the Polyomaviridae family. It causes progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease of the nervous system, which usually results in irreversible damage of the central nervous system or death within a few months. The route of primary infection is not clear, but there is evidence that the virus infects humans through the upper respiratory or gastrointestinal tract. The seroprevalence rate of JCV infection ranges from 66% to 92% of the world's population [148]. The primary infection is usually asymptomatic and believed to occur in childhood, and the virus remains latent in different sites of the body, including bone marrow and B lymphocytes. There is evidence that the virus enters the brain early in the disease and produces low-grade chronic infection of the glia cells [148]. PML has been recognized previously in patients who were heavily immunosuppressed with, for example, myeloproliferative diseases, cancers, organ transplantation, and HIV infection. Recently, the incidence of PML has increased with the use of monoclonal antibodies in the treatment of various diseases [149]. The mechanism by which JCV causes PML is unclear, but a recent study showed that JCV DNA loads were higher in the brain of non-PML patients who received IMDs than those who did not, suggesting reactivation of latent JCV in brain tissue by using IMDs [150]. Prevalence of PML in ARDs Due to the rarity of PML, data on its epidemiology in patients with ARDs are limited. A national frequency estimate of PML in ARDs, using the USA Nationwide Inpatient Sample (NIS) database of 2009, identified 43 cases of SLE, 24 of RA, and 25 of other connective tissue diseases, and the rates of PML per 100,000 discharged patients for SLE, RA, and other connective tissue disease were 4, 0.4, and 2, Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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respectively, compared with 0.2 of the general population [151]. However, this study has some limitations in that the diagnosis was made by treating physicians and the details of immunosuppressive therapy were not available, and it included only hospitalized patients. Another study in the USA used data from Medicare and Medicaid Services, and a PML incidence of 0.2 per 100,000 patients was found among 2,030,578 patients with ARDs. Of nine patients, who used bDMARDs prior to PML hospitalization, three (one receiving infliximab for inflammatory bowel disease, and the other two rituximab for RA) received them within 3 months [152]. One study found the estimated risk of PML in patients with RA receiving rituximab to be 1:25,000 users; unfortunately, this calculation was based on case reports and number of exposures, and not from a case-controlled study [153]. Data from the Swedish National Patient Register and Swedish Rheumatology Quality Register found that the incidence rate (per 100,000 patient years) of PML in the RA population was 1.0 (95% CI 0.3e2.5) compared with 0.3 (95% CI 0.1e0.6) in the general population. The rate was 0.8 (95% CI 0.2e2.5) and 2.3 (95% CI 0.1e71) among biologic-naïve patients and biologic-exposed patients, respectively [154]. This finding indicates that PML in patients with RA has a higher incident rate than that in the general population, particularly among those who receive bDMARDs. PML, ARDs, and the use of immunosuppressive therapy In 2007, a review reported the identification of 36 PML cases associated with rheumatic diseases [155]. Twenty-three patients (63.8%) had SLE, whereas non-SLE patients had Wegener's granulomatosis, dermatomyositis, RA, and systemic sclerosis. Interestingly, although the intensity of IMD therapy was highly variable within 6 months prior to the development of neurological symptoms, eight SLE and two non-SLE patients received only low-dose corticosteroids. None of these patients received bDMARDs. Later cases of PML were described in patients with rheumatic diseases, particularly RA, who received both non-bDMARDs [156] and bDMARDs, including rituximab [153], tocilizumab [157], and anti-TNFa [158]. The occurrence of PML in patients receiving rituximab is interesting. The high incidence of PML in patients with AIDS, who have markedly diminished CD4þ T-cell levels, indicates that T lymphocytes (CD4þ and JC virus CD8þ T cells) play a major role in controlling the latency of JCV. Thus, the occurrence of PML in patients treated with rituximab indicates that B cells also play a role in controlling JCV with negative effects on T-cell activation, which is known to be important in controlling JCV replication [159]. Although there is no definite therapy for PML at present, its diagnosis is particularly crucial in patients with ARDs receiving IMDs. PML must be included in the differential diagnosis of neuropsychiatric SLE or CNS vasculitis, as many patients were diagnosed as such prior to PML development. These patients have often received increased dosage of corticosteroids and IMDs, when central nervous system involvement is presumed in these diseases. There is no benefit in giving this treatment because it can cause a detrimental effect in PML. In fact, the dosage of corticosteroids or IMDs should be decreased or discontinued in order to restore the immune system and control the JCV. The diagnosis of PML should be made by detailed history, physical examination, imaging study, and presence of JCV in the cerebrospinal fluid detected by polymerase chain reaction (PCR). A negative JCV PCR does not rule out the disease, and a brain biopsy should be considered in suspicious cases [159]. Kaposi sarcoma-associated herpesvirus Kaposi sarcoma (KS) is a rare malignant tumor of endothelial and smooth muscle cells caused by Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8). The virus can be transmitted via the sexual and nonsexual route. The prevalence of KSHV varies among different parts of the world, and it is estimated to be <5% in North America, northern Europe, and Asia; 5e20% in the Caribbean and Middle East; and >50% in Africa [160]. The prevalence increases markedly among patients with untreated HIV infections or AIDS and recipients of transplanted organs. The development of KS results predominantly from reactivation of the virus, but it might be possible as a primary infection in cases of organ transplantation. Immunosuppression-associated KS and AIDS-associated KS is more severe than classical KS (in males of eastern European and Mediterranean origin) and endemic KS in Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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Africa, in that the former two types tend to have an aggressive clinical course, with mucosa, lymph node, and visceral organ involvement. Despite the wide use of corticosteroids and IMDs in ARDs, KS in these patients has been reported rarely. In a review of 25 KS patients with ARDs, reported prior to the biologic era, KS was found in patients with RA, SLE, polymyositis/dermatomyositis, Behcet's disease, and various vasculitides [161]. All of these patients received corticosteroid therapy, and seven also received IMDs (mainly MTX, azathioprine, or cyclophosphamide). KS development after initiation of corticosteroids or IMDs ranged from 6 weeks to 22 years. The mortality rate was 24%. Tumor regression usually occurred with decreasing doses of corticosteroids or IMDs, or with cytotoxic therapy. Sporadic cases of KS have been reported to be associated with anti-TNFa therapy for RA [162] and psoriatic arthritis [163], after administration of anti-TNFa for 9e16 months. KS regressed after discontinuing anti-TNFa and vinblastine treatment [163]. Interestingly, treatment with tocilizumab did not cause recurrent KS or reactivation of HHV-8 in a patient with RA who previously had KS [164]. It is not clear whether the role of routine screening for HHV-8 antibody or HHV-8 viral load in detecting reactivation of the virus prevents KS-associated IMDs from developing. Human papillomaviruses HPV is a non-enveloped dsDNA virus that has been of increasing interest as a cause of benign skin warts on the hands and feet; genital warts; and malignancies of the head, neck, and anogenital tract [165]. More than 100 genome subtypes of this virus have been identified. Type 6 and 11 are associated usually with genital warts (low risk: LR-HPV), and type 16 and 18 are major subtypes that are associated with invasive carcinoma of the cervix (high risk: HR-HPV). The virus spreads via sexual contact and infects the stratified epithelium. Inside the cell, the HPV genome integrates with host DNA, where intact virions are released when HPV-infected epithelia are sloughed. The virus can be cleared in most infected women within 1 year, but a small proportion will go on to develop persistent infection and malignancies [166]. Multiple-type and persistent HR-HPV infection are common in the high-risk population, and they increase the risk of developing invasive or high-grade squamous intraepithelial lesions (HSIL). Immunosuppressive states, increasing age, smoking, coinfection with other microorganisms, oral contraceptive use, menstruation, and menopause have been found to be associated with persistent infection [167]. Studies of HPV infection and genital cancer in patients with ARDs are limited and mostly confined to SLE. A study from Mexico found a prevalence of HPV and HR-HPV infections in SLE, RA, and healthy controls of 14.7%, 27.9%, and 30.8%, respectively, and 11.7%, 27.9%, and 26.0%, respectively. Although the prevalence in patients with SLE was lower, at about half that of healthy controls, it did not show a statistically significant difference [168]. By contrast, a recent meta-analysis showed that SLE patients had a significantly higher frequency of HR-HPV infection and a higher risk of HSIL than healthy female controls (OR 8.66, 95% CI 3.75e20.00) [169]. A study on the natural course of HPV infection in patients with SLE found a significant increase in the cumulative prevalence of HPV, HR-HPV, and multiple HPV infections over time. Preexisting HPV infection and multiple HPV infection at the time of the first incident infection were independent risk factors for persistent infection [170]. Interestingly, despite the increased frequency of HPV infection and cervical dysplasia in patients with SLE, the incidence of cervical cancer did not differ from that in the general population. Furthermore, studies on the association between IMDs use and frequency of cervical abnormalities are still inconclusive [171]. As the immunosuppressive state is associated with persistent HPV infection, the use of bDMARDs and the role of developing persistent HPV infection and cervical dysplasias in patients with ARDs should be explored. Vaccination in patients with ARDs and possible induction of autoimmunity Currently, the ACR recommends that, if possible, killed vaccine (pneumococcal, intramuscular influenza, and hepatitis B), recombinant HPV vaccine for cervical cancer, and live attenuated vaccine (herpes zoster) should be given to all patients with ARDs prior to starting IMDs [75]. Killed and recombinant HBV vaccine can be given prior to or during IMD therapy. Live attenuated vaccine is generally considered to be contraindicated, but it can be given to patients only receiving low-dose Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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immunosuppressive therapy (prednisone < 20 mg/day, MTX < 0.4 mg/kg/week, or azathioprine < 3 mg/kg/day). Those receiving higher doses than this should defer vaccination for at least 1 month after ceasing such a treatment [130]. Live attenuated vaccine should be given at least 4e6 weeks prior to commencement of bDMARDs. Information on herpes vaccination in patients with ARDs is limited. A study on RA found that only 0.4% of the patients received herpes zoster vaccine in 2007, but the percentage increased gradually to 4.1% by 2011 [125]. This low percentage might be due partly to the fear of giving live vaccine to patients taking IMDs. A large study that used the Medicare database for patients with inflammatory arthritis confirmed that the herpes zoster vaccine reduced the risk of herpes zoster by 40% in 2 years, and no such cases had occurred in patients exposed to bDMARDs at the time of vaccination or within the subsequent 42 days [122]. In a small open study of herpes zoster vaccination, 10 patients with SLE had low disease activity and received low-dose corticosteroids, hydroxychloroquine, or MTX, and none developed herpes zoster within 12 weeks post vaccination [172]. There have been recent reports of autoimmune or autoinflammatory syndrome in healthy individuals after vaccination [173,174]. The vaccine might act as an adjuvant-induced autoimmune phenomenon or syndrome in patients prone to developing autoimmune diseases [175]. Therefore, the safety issue of these vaccines in patients with definite ARDs needs to be investigated further. Summary With the widespread use of IMDs in treating ARDs over the past decade, in addition to infection, an increasing number of reports have been found on the reactivation of underlying viral infections. The clinical features of virus reactivation can sometimes mimic flare of underlying ARDs. The correct diagnosis and management of such reactivation is crucial, as increasing the dose of IMDs to treat presumed flare of underlying disease would probably be of no benefit, and it could exert a detrimental effect on the host. So far, information on the use of IMDs in patients with ARDs and underlying HBV, HCV, or HIV has been widely available, whereas that for other viruses is still limited. IMDs can be used safely in patients with anti-HBsþ, anti-HCV, and HIV (who receive HAART with a CD4 count of >200/ mm3 and HIV viral load of <60,000 copies/mm3). Antiviral therapy can usually control the reactivation of these viruses. However, the use of IFNa to treat underlying HBV and HCV infections in patients with ARDs, and the possibility of induction or exacerbation of the ARD conditions, is another concern. Use of a non-IFNa regimen in the treatment of CHC infection is increasingly acceptable. Ideally, vaccination should be given to all patients with ARDs prior to the initiation of IMDs. Use of a live vaccine is also of concern because of virus activation, but it can be used if the patient is not undergoing high-intensity immunosuppression therapy. Lastly, prescreening for underlying virus infection, particularly HBV, HCV, HIV, and HPV, and continued vigilance of its reactivation during treatment is needed. The cost and benefit of routine screening for other rare viruses have thus far not been determined.

Practice points  Latent viral infection in patients with ARDs is not uncommon  Use of IMDs can reactivate these latent viruses, causing both local and systemic manifestations, which sometimes mimic exacerbation of underlying ARDs  Recognizing viral reactivation is critical, as discontinuing IMDs restores the immune function, controls the virus, and improves conditions, whereas increased dosage or addition of new IMDs has the opposite effect  Pretreatment latent viral infection particularly for HBV, HCV, and HIV is mandatory. However, screening should also be performed for possible previous exposure to other viruses in patients with ARDs who will undergo immunosuppressive therapy. Vigilance of possible viral reactivation during IMD therapy is needed  Appropriate specialist consultation for definite diagnosis and management is needed, particularly from infectious disease specialists, for patients with ARDs who develop new multisystem diseases.

Please cite this article in press as: Louthrenoo W, Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/j.berh.2015.05.010

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Research agenda  Systematic studies are needed to identify patients at a risk of viral reactivation, and to analyze the cost-effectiveness of routine screening for all previous viral infections (other than HBV, HCV, and HIV), prior to and during IMD therapy  The efficacy and safety (particularly induction of the autoinflammatory syndrome) of vaccinating patients with ARDs receiving IMDs need to be explored  The efficacy of long-term antiviral prophylaxis for VZV infection in patients with ARDs currently taking high-dose IMDs and the contraindication to herpes zoster vaccination should be of interest.

Disclosure None. Conflict of interest None. Funding support None.

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