• Persistence of herpes virus infection in children and its role in juvenile rheumatoid arthritis (a literature review)

Persistence of herpes virus infection in children and its role in juvenile rheumatoid arthritis (a literature review)

SOVREMENNAYA PEDIATRIYA.2018.6(94):59-69; doi 10.15574/SP.2018.94.59

Berezhniy V. V., Bondarets Y. I.
Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine

The article presents data on the persistence of herpes virus infection (HVI) in children and its effect on the immune system in patients with juvenile rheumatoid arthritis (JRA). Analysis of the published works shows the adverse effects of HVI on the immune status of patients with JRA. The significance of various types of HVI and risk of its occurrence in the JRA treatment with basic and immunobiological preparations are shown.

Key words: children, herpes viruses, immune status, juvenile rheumatoid arthritis.


1. Bukhanova DV, Belov BS. (2016). Herpes zoster virus infection and rheumatic disease: Current state of the problem. Modern Rheumatology Journal. 10(3):69–76.

2. Derbasova NN. (2007). Features of immune disorders in herpetic infection of the eyes and clinical-immunological efficacy of various therapies. Abstract of dissertation for the degree of Candidate of Medical Sciences. Vladivostok: 27.

3. Zheleznikova GF. (2006). Infection and immunity: strategies from both sides. Med. Immunolog. 8(5-6): 597–614.

4. Zborovskaya I, Alexandrov A, Slyusar O. (2010). Treatment of rheumatoid arthritis patients with concomitant herpetic infection. Doctor.12:76–79.

5. Kamolov ZS. (2004). Functional activity of natural killers and production of interleukins in rheumatoid arthritis. Allergology and Immunology.5(1):95–98.

6. Karazhas NV, Malyshev NA, Rybalkina TN et al. (2007). Herpesviral infection. Guidelines. Moscow: 1–118.

7. Kireev VV, Dzhaparov AK, Musakhodzhayeva DA. (2013). Influence of the Epstein-Barr virus on immune signs of synovial fluid in rheumatoid arthritis. Immunopathology and Clinical Immunology. 5: 265–267.

8. Kramarov SA, Vygovska OV. (2013). Epstein-Barr Virus Infection in Children. Journal Actual Infectology.1:73–78.

9. Malkhanov VB, Shevchuk NE, Marvanova ZR. (2004). Cytokine status of patients with ophthalmoherpes. Questions of virology. 49 (1): 28–30.

10. Nasonov EL. (2001). Modern directions of immunological studies of chronic inflammatory and autoimmune diseases. Therapeutic Archive. 8: 43–46.

11. Petrov AV, Biloglazova KV. (2008). The frequency of infectious complication in patients with rheumatoid arthritis and persistence of Herpesviridae viruses on treatment with methotrexate and sulfasalazine. The Ukrainian Rheumatological Journal. 3(33):48–51.

12. Petrov AV, Dudar LV, Maly KD. (2004). Persistence of various infective agents in blood mononuclear leukocytes in debute of rheumatoid arthritis. Therapeutic Archive.5:32–35.

13. Pronina NA, Sviridova VS, Kologrivova EN et al. (2009). Influence of herpes simplex virus persistence upon production of cytokines by immunocompetent cells in rheumatoid arthritis. Med. Immunolog. 1(11): 91–94.

14. Redkin YuV, Odokienko AYu. (2004). Clinical-immunological features of patients with herpetic infection of I and II types. Omsk Scientific Bulletin. Medicine. 1(26):151–156.

15. Savinkov PA, Rybalkina TN, Karazhas NV et al. (2015). The role of herpesviruses and pneumocysts in the etiology of infectious diseases in children with immunosupression of various nature. Clinical microbiology and antimicrobial chemotherapy. 17(4): 251–330.

16. Safina AZ. (2004). The role of herpes viruses, mycoplasmas, chlamydia in rheumatoid arthritis and treatment with cycloferon. Abstract of dissertation for the degree of Candidate of Medical Sciences. Ufa: 24.

17. Simovanyan EV, Denisenko AV, Grigoryan MA et al. (2016). Epstein-Barr Virus Infection in Children: Improving the Diagnosis and Treatment Program. Journal Children’s Infections. 1:15–23.

18. Soboleva NG. (2009). Juvenile rheumatoid arthritis in children of the Krasnodar Territory (features of etiopathogenesis, optimization of therapeutic tactics). Abstract of dissertation for the degree of Doctor of Medical Sciences. Krasnodar: 36.

19. Soldatova EYu, Zholobova ES, Melekhina EV. (2017). The prevalence of herpes virus infection in patients with various forms of juvenile arthritis. Therapist: 6.

20. Soldatova EYu, Melekhina EV, Gorelov AV. (2017). Herpesvirus infection in patients with juvenile arthritis. Epidemiology and infection diseases. 1:46–53.

21. Khaldin AA, Gilyadov AD, Bykhanova ON. et al. (2015). Herpes zoster: modern clinical features and the principles of therapeutic management. Journal Clinical Dermatology and Venereology. 1:77–81.

22. Julish EI, Volosovets AP. (2005). Congenital and acquired TORCH infections in children. Donetsk: Regina: 216.

23. Alvarez-Lafuente R, FernandezGutierrez B, de Miguel S et al. (2005). Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction. Ann Rheum Dis. 64(9):1357—9. https://doi.org/10.1136/ard.2004.033514; PMid:16100341 PMCid:PMC1755640

24. Antonelli MA, Moreland LW, Brick JE. (1991). Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. Am J Med. 90(3): 295—8. https://doi.org/10.1016/0002-9343(91)80008-A; https://doi.org/10.1016/0002-9343(91)90568-I

25. Balandraud N, Meynard JB, Auger I et al. (2003). Epstein—Barr virus load in the peripheral blood of patients with rheumatoid arthritis: accurate quantification using real-time polymerase chain reaction. Arthritis Rheum. 48(3): 1223—1228. https://doi.org/10.1002/art.10933; PMid:12746895

26. Balandraud N, Guis S, Meynard JB et al. (2007). Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not increase Epstein-Barr virus load in patients with rheumatoid arthritis. Arthritis Rheum. 57(5): 762—7. https://doi.org/10.1002/art.22783; PMid:17530675

27. Ball RJ, Avenell A, Aucott L et al. (2015). Systematic review and meta-analysis of the sero-epidemiological association between Epstein—Barr virus and rheumatoid arthritis. Arthritis Research and Therapy. 17: 274. https://doi.org/10.1186/s13075-015-0755-6; PMid:26416719 PMCid:PMC4587583

28. Belin V, Tebib J, Vignon E. (2003). Cytomegalovirus infection in a patient with rheumatoid arthritis. Joint Bone Spine. 70(4): 303—6. https://doi.org/10.1016/S1297-319X(03)00049-6

29. Brodsky M. (1999). Stealth, sabotage and exploitation. Immunol Rev: 5—11. https://doi.org/10.1111/j.1600-065X.1999.tb01278.x; PMid:10399060

30. Curtis JR, Xie F, Yun H et al. (2016, Apr 25). Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis. pii: annrheumdis-2016—209131. doi 10.1136/annrheumdis-2016-209131.

31. Ede A, Laan R, Rood M et al. (2001). Effect of folic or folinic acid supplementation of the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, rabdomized, placebo-cjntrolled study. Arthritis Rheum. 44: 1515—1524. https://doi.org/10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7

32. Galloway JB, Mercer LK, Moseley A et al. (2013). Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 72(2): 229—34. https://doi.org/10.1136/annrheumdis-2011-201108; PMid:22532633 PMCid:PMC3595979

33. Grawford DH. (2001). Biology and disease associations of Epstein—Barr virus. Philos Trans. R. Soc. Lond. B. Biol. Sci. 356(1408): 461—473. https://doi.org/10.1098/rstb.2000.0783; PMid:11313005 PMCid:PMC1088438

34. Ikuta K, Satoh Y, Hoshikawa Y et al. (2000). Detection of Epstein—Barr virus in salivas and throat washings in healthy adults and children. Microbes Infect. 2(2): 115—120. https://doi.org/10.1016/S1286-4579(00)00277-X

35. Kasahara Y, Yachie A. (2002, Dec). Cell type specifie infection of Epstein—Barr virus (EBV) in EBV-associated hemophagocytie lymphohistiocytosis and chronic active EBV infection. Crit Rev Oncjl Hematol. 44(3): 283—294. https://doi.org/10.1016/S1040-8428(02)00119-1

36. Kelaidi C, Tulliez M, Lecoq-Lafon C et al. (2002). Long-term remission of an EBV-positive B cell lymphoproliferative disorder associated with rheumatoid arthritis under methotrexate with anti-CD20 monoclonal antibody (Rituximab) monotherapy. Leukemia. 16(10): 2173—4. https://doi.org/10.1038/sj.leu.2402588; PMid:12357380

37. Lunemann JD, Frey O, Eidner T et al. (2008). Increased frequency of EBV-specific effector memory CD8+ T cells correlates with higher viral load in rheumatoid arthritis. J Immunol. 181(2): 991—1000. https://doi.org/10.4049/jimmunol.181.2.991; PMid:18606650 PMCid:PMC2570434

38. Maksymowych WP, Suerez-Almazor ME, Buenviaje H et al. (2002). HLA and cytokine gene polymorphisms in relation to occurrence of palindromic rheumatism and its progression to rheumatoid arthritis. Journal Rheumatology. 29: 2319—2326. PMid:12415587

39. McDonald JR, Zeringue AL, Caplan L et al. (2009, May 15). Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect Dis. 48(10): 1364—71. https://doi.org/10.1086/598331; PMid:19368499 PMCid:PMC2743911

40. Nakajima A, Urano W, Inoue E et al. (2015, Jul). Incidence of herpes zoster in Japanese patients with rheumatoid arthritis from 2005 to 2010. Mod Rheumatol. 25(4): 558—61. https://doi.org/10.3109/14397595.2014.984829

41. Neidobitek G, Agathanggelou A, Herbst H et al. (1997). Ebstein—Barr vims (EBV) infection in infectious mononucleosis: vims latency, replication and phenotype of EBV-infected. J Pathol. 182(2): 151—159. https://doi.org/10.1002/(SICI)1096-9896(199706)182:2<151::AID-PATH824>3.0.CO;2-3

42. Pappas DA, Hooper MM, Kremer JM et al. (2015, Dec). Herpes zoster reactivation in patients with rheumatoid arthritis: analysis of disease characteristics and disease modifying anti-rheumatic drugs. Arthritis Care Res (Hoboken). 67(12):1671—8. https://doi.org/10.1002/acr.22628.

43. Pratesi F, Tommasi C, Anzilotti C. (2006). Deiminated Epstein—Barr virus nuclear antigen 1 is a target of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheum. 54: 733—741. https://doi.org/10.1002/art.21629; PMid:16508937

44. Quintanilla-Martinez L, Kumar S, Fend F et al. (2000). Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood. 96(2): 443—451. PMid:10887104

45. Segan J, Staples MP, March L et al. (2015, Mar.). Risk factors for herpes zoster in rheumatoid arthritis patients: the role of tumour necrosis factor-α inhibitors. Intern Med J. 45(3): 310—8. https://doi.org/10.1111/imj.12679.

46. Smitten AL, Choi HK, Hochberg MC et al. (2007, Dec. 15). The risk of herpes zoster in patientswith rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum. 57(8): 1431—8. https://doi.org/10.1002/art.23112; PMid:18050184

47. Strangfeld A, Listing J, Herzer P et al. (2009). Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA. 301(7): 737—44. https://doi.org/10.1001/jama.2009.146; PMid:19224750

48. Takeda T, Mizugaki Y, Matsubara L et al. (2000, Jun). Lytic Epstein—Barr virus infection in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 43(6): 1218—1225. https://doi.org/10.1002/1529-0131(200006)43:6<1218::AID-ANR4>3.0.CO;2-2

49. Toussirot E, Roudier I. (2008). Epstein—Barr in autoimmune diseases. Best Pract Res Clin Rheumatol. 22(5): 883—896. https://doi.org/10.1016/j.berh.2008.09.007; PMid:19028369

50. Winthrop KL, Yamanaka H, Valdez H et al. (2014, Oct.). Herpes Zoster and Tofacitinib Therapy in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 66(10): 2675—84. https://doi.org/10.1002/art.38745.

51. Wolfe F, Michaud K, Chakravarty EF. (2006). Rates and predictors of herpes zoster in patients with rheumatoid arthritis and noninflammatory musculoskeletal disorders. Rheumatology (Oxford). 45(11): 1370—5. https://doi.org/10.1093/rheumatology/kel328; PMid:17003175

52. Yun H, Xie F, Delzell E et al. (2015, May). Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy. Arthritis Care Res (Hoboken). 67(5): 731—6. https://doi.org/10.1002/acr.22470.

53. Zaher SS, Sandinha T, Roberts F et al. (2005). Herpes simplex keratitis misdiagnosed as rheumatoid arthritis-related peripheral ulcerative keratitis. Cornea. 24(8): 1015—7. https://doi.org/10.1097/01.ico.0000159758.36230.c1; PMid:16227854

Article received: Mar 17, 2018. Accepted for publication: Sep 27, 2018.