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Nat Rev Rheumatol. Author manuscript; available in PMC 2011 Aug 12.
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PMCID: PMC3155180

Tumor necrosis factor blockade and the risk of viral infection

Seo Young Kim, MD, MSCE and Daniel H. Solomon, MD, MPH


Tumor necrosis factor (TNF)-α blockers have been widely used to treat rheumatoid arthritis and other inflammatory diseases. An increased risk of tuberculosis and opportunistic infections with TNF-α blockers has been well reported because of the primary role of TNF-α in host defense and immune response. However, little is known about the association between TNF-α blockers and viral infections. Because interferon-γ and TNF-α play critical roles in the control of viral infection, depletion of TNF by treatment with TNF-α blockade may facilitate the risk of or reactivation of viral infection. Several large observational studies have recently found an increased risk of herpes zoster in patients receiving TNF-α blockers for rheumatoid arthritis. This review draws attention to several important viral infections such as human immunodeficiency, varicella-zoster and Epstein-Barr viruses, cytomegalovirus, and human papillomavirus in patients receiving TNF-α blocking therapy, their implications in clinical practice, and possible preventative approach with vaccination.

Keywords: tumor necrosis factor-alpha, rheumatoid arthritis, inflammatory bowel disease, infection, viral disease, vaccination, adalimumab, etanercept, infliximab, tumor necrosis factor-alpha blocker


Tumor necrosis factor (TNF)-α plays an essential role in host defense and immune response 1. TNF receptors (TNFR) are found on virtually all cell types and TNF-α affects many physiologic processes. TNF-α blockers effectively treat rheumatoid arthritis (RA) and several other chronic inflammatory conditions. The increasingly widespread use of these agents highlights the importance of understanding their safety. Much attention has been paid to the risks of opportunistic infections (i.e., tuberculosis and fungal infections) 2, 3. Some conflicting data exist on the association between the use of TNF-α blockers and serious infection 4-6. A recent meta-analysis by Bongartz et al reported that the number needed to harm for up to one year of therapy with infliximab or adalimumab was 59 (95% confidence interval (CI): 39-125) for serious infections 7. Most prior studies have focused on bacterial or opportunistic infections, with few assessing a possible association between viral infections and these agents. Since interferon-γ and TNF-α play critical roles in the control of viral infection – recruiting and activating macrophages, NK cells, T cells, and antigen presenting cells –depletion of TNF by treatment with TNF-α blockade may facilitate the risk of or reactivation of viral infection 8. We reviewed several important viral infections and their possible link with these agents. Viral hepatitis was not inclu9ded because it has recently been reviewed 10, 11.

A. Human Immunodeficiency Virus (HIV) infection

TNF is involved in the pathogenesis of HIV infection, but, to date, the exact role of TNF-α in HIV infection is not completely understood 9. A positive association between activation of the TNF system in vivo and progression of HIV-related clinical disease has been reported 12, 13. TNF and death receptors such as Fas ligand are directly or indirectly involved in the activation of T cell apoptotic processes in HIV infection 14-16. Several studies proposed the important role of TNFR signaling in HIV infection 14, 16, 17. Both TNFR1 and TNFR2 can induce apoptosis in peripheral T cells among HIV-infected persons, involving both CD4 and CD8 T cells 14.

Several case reports showed successful use of TNF-α blocking drugs in HIV-infected patients for chronic inflammatory conditions, including Crohn’s disease (CD), psoriatic arthritis (PsA), and RA (Table 1) 18-28. Most patients in these reports concomitantly received HAART. Infliximab, ranging 2 to 5 mg/kg per infusion, achieved marked clinical improvement without causing serious infection or worsening the status of HIV infection 19-22, 26, 27. No serious infectious complication or increase in the HIV viral load was noted in most cases where etanercept, either 50 mg weekly or 25 mg twice weekly, was administered 23-25, 27, 28. Successful outcomes with etanercept were noted even in patients with both HIV and viral hepatitis infection 24, 25. In contrast, Aboulafia et al reported on a 45-year-old male with HIV and PsA, who died of severe bacterial infection 4 months after the use of etanercept 18. In this case, the patient’s CD4 T cell count and HIV viral load remained stable. His skin lesions and arthritis improved significantly, but he developed recurrent polymicrobial bacterial infections. Less information is available regarding the safety of adalimumab in HIV-infected patients. Three HIV-positive patients with concomitant PsA in a study by Cepeda et al achieved partial clinical response to adalimumab while their CD4 counts and HIV viral loads remained stable 27. However, it is unknown whether the relative safety of TNF-α blocking agents in these cases can be generalized to other HIV-infected patients. Until there is a better understanding of the long-term safety of TNF- α blockers in this specific population, clinicians should avoid use of these drugs in HIV-infected patients. Under specific circumstances where TNF- α blockers are clinically needed with no other alternative treatment options, the use of these drugs should be extremely cautious with close monitoring of CD4 counts, viral loads, and any clinical signs and symptoms for infection.

Table 1
Use of TNF-α blockers in Human Immunodeficiency Virus (HIV)-infected patients

B. Varicella-Zoster Virus (VZV) infection

VZV is the cause of primary varicella, herpes zoster and post-herpetic neuralgia. Primary varicella infection is common and usually benign in children. However, disseminated varicella infection in adults and particularly immunocompromised patients can be severe and potentially fatal 29. In the general population, the incidence of herpes zoster, caused by reactivation of VZV in sensory nerve roots, is reported at 1.2 to 4.8 cases per 1,000 person-years 30, 31. Patients with compromised cell-mediated immunity due to aging, immunosuppressive agents, or concomitant illness are at an increased risk for development of herpes zoster 31, 32. Severity of herpes zoster is related to the degree of immunocompetence, evidenced by greater severity among patients with organ transplantations, lymphoproliferative diseases or the acquired immunodeficiency syndrome (AIDS) 33.

It has been noted that herpes zoster is more common in patients with systemic lupus erythematosus (SLE) and RA, because of their impaired immune system as well as medications to treat the rheumatic conditions 34-37. In a recent study from the Consortium of Rheumatology Researchers of North America (CORRONA) registry, VZV infection was the most frequent opportunistic infection – 44% of all cases of opportunistic infections — in patients who received methotrexate (MTX), TNF-α blockers or other disease modifying anti-rheumatic drugs (DMARDs) 38.

A retrospective cohort study using the U.S. Veterans Affairs Health system data demonstrated an elevated incidence of herpes zoster in RA – 9.96 cases per 1,000 patient-years 39. Correlates of herpes zoster include older age, glucocorticoid use, traditional and biologic DMARDs including methotrexate, leflunomide, azathioprine, cyclophosphamide, cyclosporine, anakinra and TNF-α blockers, malignancy, chronic lung disease, renal failure, and liver disease. Of the 96 patients treated with TNF-α blockers developed herpes zoster. Among the TNF-α blockers, etanercept (hazard ratio (HR) 0.62, 95% CI: 0.40–0.95) and adalimumab (HR 0.53, 95% CI 0.31–0.91) appeared to have a lower risk of herpes zoster, compared with infliximab (HR 1.32, 95% CI 0.85-2.03). A prospective study using the data in the German biologics register reported a significantly increased risk of herpes zoster in patients receiving treatment with the monoclonal antibodies – infliximab and adalimumab – (HR, 1.82, 95% CI 1.05-3.15), even after adjusting for age, RA severity, and glucocorticoid use 40. Notably, no significant association was found for etanercept use (HR 1.36, 95% CI 0.73-2.55) 40.

Several case reports and retrospective studies reporting VZV infection in patients who received TNF-α blocker treatment for inflammatory conditions are listed in Table 2 40-51. In the majority of the reported cases, the patients were treated with TNF-α blockers and concomitant immunosuppressive agents such as MTX and azathioprine for a period ranging 1 month. As noted in Table 2, serious morbidity and mortality from VZV infection can occur in patients who received treatment with TNF-α blockers. Of the 6 disseminated primary varicella infection cases 44, 45, 47-49, 52, 1 death occurred in a 26-year-old male patient with CD who received the first infusion of infliximab (5 mg/kg) 44. Immunization with the VZV vaccine is an effective approach to prevent both primary varicella infection and herpes zoster. However, the VZV vaccine is a live, attenuated vaccine generally contraindicated in immunocompromised patients. The use of the VZV vaccine in such patients is discussed further below.

Table 2
Cases of varicella zoster virus (VZV) infection following TNF-α blocking therapy

C. Epstein-Barr Virus (EBV) infection

EBV, also known as HHV-4, is one of the most common human viruses infecting as many as 95% of adults aged 35 to 40 years in the U.S 53. EBV causes infectious mononucleosis, Burkitt’s lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disease (LPD) 33. The relationship between EBV and autoimmune diseases are not completely understood, although EBV has been considered as a possible cause of several autoimmune diseases for many years 54. Antibodies to EBV are elevated in patients with RA, SLE, or Sjogren’s syndrome 55. A study by Balandraud et al reported that peripheral blood EBV viral load was associated with high disease activity in RA 56. However, neither MTX nor TNF-α blockers significantly modified EBV load over time 56.

Several case reports in the literature described EBV-related conditions associated with TNF-α blocking therapy. Sari et al reported a 20-year-old male with juvenile ankylosing spondylitis, who developed atypical infectious mononucleosis following infliximab treatment for 8 weeks 57. This patient presented with fatigue, malaise, abdominal discomfort, weight loss and lymphadenopathy, however fever, pharyngitis, and lymphocytosis were not present. His serologic test revealed positive IgM antibodies to the viral capsid antigen of EBV, also confirmed in the lymph node biopsy. The authors concluded that blockade of TNF-α might have masked the typical symptoms of infectious mononucleosis. In a case report by Park et al, a 65-year-old Korean female with RA for 4 years developed multiple enlarged lymph nodes, elevated acute phase reactants and anemia several weeks after initiation of etanercept 25mg twice weekly 58. Subsequently, she was diagnosed with EBV-associated diffuse LPD, which gradually resolved after stopping etanercept. Another case of EBV-associated LPD was reported in a 63-year-old Japanese patient with RA following a month of infliximab (3mg/kg) therapy 59. In this case, cessation of infliximab therapy also resulted in a dramatic regression of LPD without further treatment. Losco et al described a case of EBV-associated, diffuse large B-cell lymphoma of the ileum in a 42-year-old male with CD, after long-term use of azathioprine and a single dose of infliximab (5mg/kg) 60. His treatment was successful with a surgery and a course of chemotherapy. The use of TNF-α blockers is probably not the sole cause of EBV infection. Nevertheless, cessation of the drugs should be considered when suspected, as these drugs may indirectly increase risk of infection or reactivation of EBV.

D. Cytomegalovirus (CMV) infections

CMV or HHV-5 is a common viral pathogen that infects 40-60% of the population in developed countries 33, 61. Several cases of CMV infection complicating TNF-α blocking therapy were reported (Table 3). Of those, 4 cases occurred in patients with inflammatory arthritis 62-65. In a case by Petersen et al, a 37-year-old male with a long standing history of psoriasis and PsA developed a primary CMV infection following a month of therapy with etanercept 50mg twice weekly (a standard initial dose for plaque psoriasis) 63. His clinical presentations included fever, pneumonia, abnormal liver function tests, and otitis media. After discontinuation of etanercept, the patient recovered spontaneously with no antiviral therapy. Six months later, he was restarted on etanercept without CMV reactivation. Except for this patient, all other patients in Table 3 were treated with infliximab for either IBD or inflammatory arthritis 62, 64-71. Haerter et al reported a case of severe CMV retinitis in a 57-year-old female with a longstanding history of RA who received infliximab (3mg/kg) for 2 years 62. This patient was concomitantly on oral cyclophosphamide 150mg daily and azathioprine 150mg daily due to refractory RA. Her initial episode of retinitis in the right eye was treated with intravenous ganciclovir followed by a maintenance therapy with oral valganciclovir. However, she developed a recurrent CMV retinitis in the contralateral eye 5 weeks after stopping valganciclovir. A case of severe CMV colitis was noted in a 25-year-old male with Behcet’s disease after the 3rd dose of infliximab (5mg/kg) 65. He was previously treated with monthly intravenous cyclophosphamide, interferon, cyclosporine and azathioprine. His colitis resolved with cessation of infliximab and intravenous ganciclovir for a month. In a study by Pontikaki et al, one of 151 patients with juvenile idiopathic arthritis (95 on etanercept and 56 on infliximab) developed CMV pulmonary infection following infliximab therapy 64. Most patients in Table 3 were using more than one immunosuppressive drug, and thus, it is difficult to determine whether the use of TNF-α blockers was directly involved in CMV infection. Nonetheless, TNF-α blockade can theoretically put patients at an increased risk of this viral infection.

Table 3
Cases of cytomegalovirus (CMV) infection following TNF-α blocking therapy

E. Kaposi’s sarcoma-associated herpesvirus infection

Kaposi’s sarcoma, caused by HHV-6, is a vascular, multicentric malignant tumor 72, 73. It is rare and usually associated with the AIDS and organ transplantations 74. A number of cases of Kaposi’s sarcoma have been noted in non-AIDS patients on immunosuppressive therapy for the rheumatic diseases such as RA, SLE and vasculitis 75-78. There is almost no data supporting an association between TNF-α blocking therapy and Kaposi’s sarcoma, with only one case of Kaposi’s sarcoma reported in a patient with RA who received 12 doses of infliximab (3mg/kg). One prospective study of 60 patients with CD found no patients turning positive by polymerase chain reaction for HHV-6 during 14-weeks of follow-treatment. 79

F. Human papillomavirus (HPV) and molluscum contagiosum virus (MCV) infection

Table 4 summarizes cases of cutaneous infections with either HPV or MCV in patients who received TNF-α blocking therapy (3 patients with infliximab and 2 patients with etanercept) 80-83. Little is known about the incidence or prevalence of HPV infection in patients with rheumatic diseases although anogenital HPV infection is the most common sexually transmitted disease in the U.S 84, 85. HPV types 1, 2, and 4 cause verrucae vulgares, also known as benign warts, on the hands and feet. HPV types 6 and11 usually cause benign condylomata acuminata, while types 16, 18, 31, and 33 cause precancerous, high-grade squamous intraepithelial neoplasia and invasive carcinomas of the anogenital tract. The majority of infections with HPV are subclinical. In 80%, the infection resolves spontaneously within a year as a result of a cellular immune response 85. The risk of persistent HPV infection, particularly with oncogenic genotypes, may be associated with factors such as age, smoking, hormonal status, coexisting infections, and family history 86. Although there is no direct evidence linking host immunologic response to risk of HPV persistence, viral reactivation from a latent state in immunocompromised patients has been noted 87, 88. An increased risk of cervical dysplasia, HPV infection and persistence has been repeatedly reported in patients following kidney, lung, and stem cell transplantation 89-92. A study by Kane et al found that women with IBD were also more likely to have higher-grade cervical dysplasia caused by HPV infection than controls (odds ratio (OR) 4.3, 95% CI 2.2-10.5). In addition, those women exposed to immunosuppressive therapy were more likely to have abnormal Pap smears than controls (OR 4.5, 95% CI 1.5-12.3) as well as unexposed IBD patients (OR 1.9, 95% CI 1.1-12.1) 93. Given the available, albeit limited, data in the literature, it is possible that use of immunosuppressive agents including TNF-α blockers increases the risk of persistent HPV infection and ultimately cervical cancer. Future study should determine the optimal screening strategy for high-risk HPV infection or cervical cancer and the potential benefit of HPV vaccine in immunocompromised patients with rheumatic disease, particularly among those receiving TNF-α blockers. Molluscum contagiosum is another viral infection of the skin or occasionally of the mucous membranes. It is more common in children or in adults with HIV or other immunosuppressed conditions 94.

Table 4
Cases of human papilloma virus (HPV) and molluscum contagiosum virus (MCV) infection following TNF-α blocking therapy

G. JC virus infection or progressive multifocal leukoencephalopathy (PML)

PML, a fatal demyelinating disease of the central nervous system, is a very rare disease. The incidence has increased with the AIDS pandemic and the more common use of immunosuppressive drugs for organ transplantation or rheumatic diseases 95. It is caused by reactivation of the JC virus, a type of polyomavirus 96. As of May 2009, a total of 10 cases of PML were reported in patients who took natalizumab, a monoclonal antibody against α4 integrin, used for multiple sclerosis and CD 97, 98. Use of other monoclonal antibodies-- efalizumab, rituximab, and infliximab-- and various transplant drugs such as tacrolimus and mycophenolate has been associated with PML cases 99-102. A recent study reviewed 57 cases of PML after rituximab therapy between 1997 and 2008 103. Of those, 2 patients had SLE and 1 had RA. A retrospective cohort study of 734 patients with IBD on infliximab showed that a fatal case of PML after the use of both natalizumab and infliximab 104. Yamamoto et al reported a case of leukoencephalopathy in 74-year-old Japanese patient with RA on etanercept. Although this patient had characteristics of PML, the PCR for the JC virus-DNA was negative in the cerebrospinal fluid (CSF) 105.

No definite case of PML has been reported following the use of etanercept or adalimumab in published literature. However, the diagnosis of PML is easily missed without a high degree of suspicion. In some cases, characteristic evidence of the damage caused by PML in the brain can be detected on MRI scans 95, 98. PML can be confirmed by quantitative PCR for JC virus DNA in the CSF or in a brain biopsy specimen 95. The PCR test performed on the CSF has a sensitivity between 76-98% and a specificity of 98-99% 106, 107. Mohan et al reported a series of 19 patients with demyelinating neurologic events following treatment with TNF-α blockers (17 for etanercept and 2 for infliximab) for rheumatic diseases 108. None was diagnosed as PML, but lumbar puncture was only performed in 1 patient and brain biopsy was done in just 2 patients. Jarand et al described 3 cases of neurological complications related to the use of infliximab, but with no specific information on the serology of JC virus 109. Although JC virus infection is very rare and may not be associated with TNF-α blockers, physicians should still maintain a very high level of suspicion for any immunosuppressed patient with new neurologic symptoms, such as disorientation, ataxia, speech disturbance or visual loss.

E. Other viral-associated infections

A few case reports have been published regarding viral pneumonia in patients who received TNF-α blockers for chronic inflammatory diseases. Smith et al reported that, after using etanercept for RA, a 54-year-old female developed severe parainfluenza type 3 pneumonia requiring mechanical ventilation and a prolonged hospitalization for 3 weeks 110. A case of severe adenovirus pneumonia following the first dose of infliximab (3 mg/kg) was reported in a 35-year-old male with CD 111. Kang et al also described a case of severe adenovirus pneumonia in a 55-year-old female with RA who took etanercept 25 mg twice weekly for 2 years 112. In both cases of adenovirus pneumonia, the patients recovered with antiviral treatment and intravenous immunoglobulin G after prolonged hospitalizations. Most respiratory viral infections are self-limited in immunocompetent subjects. However, the possibility of disseminated and fatal respiratory viral infection should be considered in the differential diagnosis for immunocompromised patients, to ensure appropriate treatments for these infections.

F. Vaccinations against virus infections

Table 5 summarizes all available viral vaccines recommended for adults in the U.S. The appropriate vaccination of immunosuppressed patients including those with rheumatic disease is crucial to decrease morbidity and mortality related to vaccine-preventable infectious diseases. In 2008, the American College of Rheumatology (ACR) published their recommendations for the use of non-biologic and biologic DMARDs in RA 113. The ACR Task Force Panel recommended periodic pneumococcal vaccinations and annual influenza vaccinations for all patients receiving non-biologic and biologic DMARDs and completion of a hepatitis B vaccination series for the patients with risk factors. These recommendations are in accordance with the Centers for Disease Control and Prevention (CDC) general recommendations 117. Live-virus vaccines such as inhaled influenza and varicella-zoster vaccines are contraindicated in immunosuppressed patients 113, 114. Based on the recommendations of the Advisory Committee on Immunization Practices (ACIP), patients with congenital immunodeficiency, hematologic malignancy, generalized malignancy or therapy with alkylating agents, antimetabolites, radiation or high dose of corticosteroids – 2mg/kg of body weight or a total of 20mg/day of prednisone— are considered severely immunocompromised 114, 115. With regard to patients on high-dose, systemic corticosteroids for more than 2 weeks to control rheumatic diseases, a live-virus vaccine should be avoided during the therapy, although it can be given after stopping the therapy for at least 3 months 114, 115. Patients receiving systemic corticosteroid therapy less than 14 days, low-to-moderate dose of corticosteroids, local steroids injection, low-dose methotrexate (less than 0.4 mg/kg/week) or azathioprine less than 3.0 mg/kg/day can receive a live-virus vaccine 115. The ACR Task Force Panel recommends live-virus vaccines including zoster vaccine should also be avoided in patients receiving biologic therapy 113. The ACR Hotline suggested that rheumatologists should avoid the zoster vaccine in patients actively receiving TNF blockers, as well as abatacept, rituximab and anakinra or delay the initiation of biologic therapy until at least two weeks after the zoster vaccine is given in some patients 116. The American Society of Transplantation 2004 guidelines for vaccination of solid organ transplant candidates recommends varicella, measles, mumps, rubella, and rabies vaccines before organ transplantation 113, 117. No guideline for the use of vaccination prior to initiating biologic therapy for rheumatic diseases has been issued yet. Nonetheless, it is important to note that a physician should determine the degree to which an individual patient is immunocompromised prior to administering a live-virus vaccine.

Table 5
Available viral vaccines recommended for adults in the United States * 122

Over the last several years, two new vaccines against viral infections were licensed in the U.S. Zostavax, a live, attenuated varicella-zoster vaccine, has been approved for prevention of herpes zoster and post-herpetic neuralgia in 2006. Currently, it is recommended for all immunocompetent persons aged 60 years and older, regardless of history of varicella (chickenpox) or herpes zoster 118. As well, an inactivated, quadrivalent (type 6, 11, 16, and 18) HPV vaccine, Gardasil, was approved for females aged 9 to 26 years in the U.S 84. A bivalent (type 16 and 18) HPV vaccine is not yet available in the U.S. This vaccine is most efficacious when given before the onset of sexual activity, but some benefit may exist in protecting against the other genotypes even in a patient with preexisting HPV infection. A recent randomized, double-blind trial reported the efficacy of the quadrivalent HPV vaccine in women aged 25 to 45 years with no history of genital warts and cervical disease after 26 months of follow-up using a composite endpoint comprising cervical or external genital disease or type-specific infection that had persisted for at least 6 months 119. Due to the lack of long-term studies at the present time, the duration of immunogenecity is not known. It is also unknown whether this vaccine is safe and effective in immunosuppressed patients 120. Further studies examining the efficacy and safety of the newer vaccines in patients with immunocompromising conditions including organ transplantation and immunosuppressive therapy for rheumatic diseases are needed 121. It may be reasonable to offer both immunizations for patients before initiation of the immunosuppressive therapy unless contraindicated according to the CDC recommendations 122.


TNF-α blockade seems clearly associated with tuberculosis and opportunistic infections; however the associations between TNF-α blockers and most viral infections have not been systematically studied. The multitude of case reports should raise the suspicion for viral infections for physicians recommending these agents for systemic inflammatory conditions. Given the existence of bias and confounding in observational studies and case series, systematic reviews and meta-analyses of randomized clinical trials may be able to provide better information on potential links between TNF-α blockers and several important viral infections. Vaccination with inactivated viral vaccines is safe even in immunocompromised patients although the antibody response may be altered. Future research should evaluate the effectiveness and safety of viral vaccinations in patients with rheumatic disease on immunosuppressive therapy. Nonetheless, vigilant screening and selection of patients appropriate for immunization with both inactivated and live-virus vaccines is required in routine clinical practice. Rheumatologists should be aware of the potential for viral infection or reactivation in therapy with TNF-α blockers as discussed in this review. Education and close surveillance of patients on TNF-α blockers is critical for timely diagnosis and management of these potentially fatal infections.

Key points

  • [arrowhead] Little is known about the association between TNF-α blockers and viral infections.
  • [arrowhead] TNF-α blockade may facilitate the risk of or reactivation of viral infection through several mechanisms.
  • [arrowhead] Several successful cases of TNF-α blocking therapy in HIV patients were reviewed.
  • [arrowhead] Cases of infection with varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, human papillomavirus and JC viruses in patients who received TNF-α blocking therapy were reviewed.
  • [arrowhead] Currently available viral vaccines and the guidelines for adults were summarized.


Financial supports or conflicts disclosure:

  • S Kim: NIH (T32 AR 055885)
  • DH Solomon: NIH (K24 AR055989, P60 AR047782, R21 DE018750, and R01 AR056215); research support from Abbott Immunology and Amgen; He has also received salary support from BMS for an educational course on clinical research in Rheumatology.

Search Strategy

Data for this review were identified by searching electronic databases -- MEDLINE and EMBASE (from 1995 to May 2009) -- and references from relevant articles. The following search terms were used: Tumor necrosis factor-alpha, adalimumab, infliximab, etanercept, rheumatic disease, inflammatory bowel disease, psoriasis, virus diseases or viral infection, zoster or herpes zoster, varicella or chickenpox, cytomegalovirus, herpesvirus 4, human or Epstein-Barr virus, infectious mononucleosis, influenza vaccines or influenza or flu, HIV or human immunodeficiency virus, parvovirus or parvovirus B19, papillomavirus Infections or human papilloma virus, and condylomata acuminata. Only English language articles were reviewed.

Contributor Information

Seo Young Kim, Clinical Fellow, Division of Rheumatology, Immunology, and Allergy; Postdoctoral Fellow, Division of Pharmacoepidemiology, Brigham and Women’s Hospital, Boston MA.

Daniel H. Solomon, Associate Professor, Harvard Medical School; Associate Physician, Divisions of Rheumatology, Immunology, and Allergy and of Pharmacoepidemiology, Brigham and Women’s Hospital, Boston MA.


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