Top

Clinical Rheumatology

Published in:

01-09-2019 | Shingles | Original Article

Humoral immunity to varicella zoster virus is altered in patients with rheumatoid arthritis

Authors: Marco Krasselt, Christoph Baerwald, Uwe G. Liebert, Olga Seifert

Published in: Clinical Rheumatology | Issue 9/2019

Abstract

Introduction

The prevalence of herpes zoster (HZ) is high in patients with rheumatologic diseases. The incidence in patients with rheumatoid arthritis (RA) is at least twice as high as in healthy people. Nevertheless, little is known about humoral immunity against varicella zoster virus (VZV), in particular in patients with RA.

We, therefore, aimed to retrospectively compare VZV antibody concentrations in a collective of patients with RA in a German outpatient clinic with age- and sex-matched controls without RA.

Methods

We included n = 247 patients with RA from one single university centre as well as n = 250 age- and sex-matched controls from the in-house routine in this retrospective analysis. The concentration of VZV IgG antibody concentration was either available from the records or was measured using an enzyme-linked immunosorbent assay (ELISA). Additionally, avidity for specific IgG was analysed for some of the samples. The antibody concentrations have been compared between the two groups. Moreover, a consecutive subgroup analysis after stratification by age was performed.

Results

A total of 68.4% (n = 169) of the included patients were treated with conventional synthetic DMARDs, either as monotherapy or in combination. Biological originator DMARDs were used in 45.8% (n = 113) of the patients, with the majority (85%, n = 96) of them being on tumour necrosis factor (TNF)–inhibiting agents. As the main result of this study, antibody titres for VZV were found to be significantly lower in RA patients compared with healthy controls (p < 0.0001). The observed difference was most pronounced for the older patients being in the sixth and seventh decade. Antibody avidity was high in both groups with a significantly higher avidity among the controls (p = 0.0006).

Conclusions

A possible explanation for the low VZV antibody concentration in RA patients might be premature immunosenescence, which most likely also effects the B cell compartment and humoral immunity. This thesis is emphasised by the significantly higher antibody avidity among the controls. The data also suggest that the increased HZ risk is a consequence of a poor humoral immunity. The available HZ vaccinations should contribute to decreasing the elevated HZ risk in RA patients.

Key Points

• Humoral immunity to varicella zoster virus seems to be reduced in patients with RA.

• This impaired immunity might contribute to the increased herpes zoster susceptibility in RA patients.

• An accelerated immunosenescence in RA could be causative for this finding.

Rondaan C, de Haan A, Horst G, Hempel JC, van Leer C, Bos NA, van Assen S, Bijl M, Westra J (2014) Altered cellular and humoral immunity to varicella-zoster virus in patients with autoimmune diseases. Arthritis Rheumatol 66(11):3122–3128. https://doi.org/10.1002/art.38804 CrossRefPubMed

Veetil BM, Myasoedova E, Matteson EL, Gabriel SE, Green AB, Crowson CS (2013) Incidence and time trends of herpes zoster in rheumatoid arthritis: a population-based cohort study. Arthritis Care Res (Hoboken) 65(6):854–861. https://doi.org/10.1002/acr.21928 CrossRef

Kimberlin DW, Whitley RJ (2007) Varicella-zoster vaccine for the prevention of herpes zoster. N Engl J Med 356(13):1338–1343. https://doi.org/10.1056/NEJMct066061 CrossRefPubMed

Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan ISF, Wang WWB, Annunziato PW, Silber JL (2005) A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352(22):2271–2284. https://doi.org/10.1056/NEJMoa051016 CrossRefPubMed

Barbosa CM, Terreri MT, Rosario PO, de Moraes-Pinto MI, Silva CA, Hilario MO (2012) Immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus. Clin Exp Rheumatol 30(5):791–798PubMed

Zhang J, Xie F, Delzell E, Chen L, Winthrop KL, Lewis JD, Saag KG, Baddley JW, Curtis JR (2012) Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases. JAMA 308(1):43–49. https://doi.org/10.1001/jama.2012.7304 CrossRefPubMedPubMedCentral

Zhang J, Delzell E, Xie F, Baddley JW, Spettell C, McMahan RM et al (2011) The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study. Arthritis Res Ther 13(5):R174. https://doi.org/10.1186/ar3497 CrossRefPubMedPubMedCentral

Willis ED, Woodward M, Brown E, Popmihajlov Z, Saddier P, Annunziato PW, Halsey NA, Gershon AA (2017) Herpes zoster vaccine live: a 10year review of post-marketing safety experience. Vaccine 35(52):7231–7239. https://doi.org/10.1016/j.vaccine.2017.11.013 CrossRefPubMedPubMedCentral

Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang SJ, Diez-Domingo J et al (2016) Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med 375(11):1019–1032. https://doi.org/10.1056/NEJMoa1603800 CrossRefPubMed

10.

Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barberà J, Vesikari T, Watanabe D, Weckx L, Zahaf T, Heineman TC (2015) Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 372(22):2087–2096. https://doi.org/10.1056/NEJMoa1501184 CrossRefPubMed

11.

Mok CC (2018) Herpes zoster vaccination in systemic lupus erythematosus: the current status. Hum Vaccin Immunother 15:1–4. https://doi.org/10.1080/21645515.2018.1514228 CrossRef

12.

Krasselt M, Ivanov JP, Baerwald C, Seifert O (2017) Low vaccination rates among patients with rheumatoid arthritis in a German outpatient clinic. Rheumatol Int 37(2):229–237. https://doi.org/10.1007/s00296-016-3608-y CrossRefPubMed

13.

Krasselt M, Baerwald C, Seifert O (2018) Insufficient vaccination rates in patients with systemic lupus erythematosus in a German outpatient clinic. Z Rheumatol 77(8):727–734. https://doi.org/10.1007/s00393-017-0410-5 CrossRefPubMed

14.

van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, Emery P, Geborek P, Ioannidis JPA, Jayne DRW, Kallenberg CGM, Muller-Ladner U, Shoenfeld Y, Stojanovich L, Valesini G, Wulffraat NM, Bijl M (2011) EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 70(3):414–422. https://doi.org/10.1136/ard.2010.137216 CrossRefPubMed

15.

Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham WW, Paulus HE, Suarez-almazor M, Bombardier C, Dougados M, Khanna D, King CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG (2012) 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 64(5):625–639. https://doi.org/10.1002/acr.21641 CrossRef

16.

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588. https://doi.org/10.1136/ard.2010.138461 CrossRefPubMed

17.

von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP et al (2007) The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Epidemiology 18(6):800–804. https://doi.org/10.1097/EDE.0b013e3181577654 CrossRef

18.

Krasselt M, Baerwald C (2014) The current relevance and use of prednisone in rheumatoid arthritis. Expert Rev Clin Immunol 10(5):557–571. https://doi.org/10.1586/1744666X.2014.904746 CrossRefPubMed

19.

Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR, Caulfield MJ, Irwin MR, Smith JG, Clair J, Chan ISF, Williams H, Harbecke R, Marchese R, Straus SE, Gershon A, Weinberg A, Veterans Affairs Cooperative Studies Program Shingles Prevention Study Investigators (2008) Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis 197(6):825–835. https://doi.org/10.1086/528696 CrossRefPubMedPubMedCentral

20.

Levin MJ, Smith JG, Kaufhold RM, Barber D, Hayward AR, Chan CY, Chan ISF, Li DJJ, Wang W, Keller PM, Shaw A, Silber JL, Schlienger K, Chalikonda I, Vessey SJR, Caulfield MJ (2003) Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-dose VZV vaccine. J Infect Dis 188(9):1336–1344. https://doi.org/10.1086/379048 CrossRefPubMed

21.

Blaese RM, Grayson J, Steinberg AD (1980) Increased immunoglobulin-secreting cells in the blood of patients with active systemic lupus erythematosus. Am J Med 69(3):345–350. https://doi.org/10.1016/0002-9343(80)90003-0 CrossRefPubMed

22.

Krasselt M, Baerwald C (2017) Sex, symptom severity, and quality of life in rheumatology. Clin Rev Allergy Immunol. https://doi.org/10.1007/s12016-017-8631-6

23.

Smitten AL, Choi HK, Hochberg MC, Suissa S, Simon TA, Testa MA, Chan KA (2007) The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum 57(8):1431–1438. https://doi.org/10.1002/art.23112 CrossRefPubMed

24.

Pappas DA, Hooper MM, Kremer JM, Reed G, Shan Y, Wenkert D, Greenberg JD, Curtis JR (2015) Herpes zoster reactivation in patients with rheumatoid arthritis: analysis of disease characteristics and disease-modifying antirheumatic drugs. Arthritis Care Res (Hoboken) 67(12):1671–1678. https://doi.org/10.1002/acr.22628 CrossRef

25.

Liao TL, Chen YM, Liu HJ, Chen DY (2017) Risk and severity of herpes zoster in patients with rheumatoid arthritis receiving different immunosuppressive medications: a case-control study in Asia. BMJ Open 7(1):e014032. https://doi.org/10.1136/bmjopen-2016-014032 CrossRefPubMedPubMedCentral

26.

Winthrop KL, Curtis JR, Lindsey S, Tanaka Y, Yamaoka K, Valdez H, Hirose T, Nduaka CI, Wang L, Mendelsohn AM, Fan H, Chen C, Bananis E (2017) Herpes zoster and Tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol 69(10):1960–1968. https://doi.org/10.1002/art.40189 CrossRefPubMedPubMedCentral

27.

Curtis JR, Xie F, Yang S, Bernatsky S, Chen L, Yun H, Winthrop K (2018) Herpes zoster in tofacitinib: risk is further increased with glucocorticoids but not methotrexate. Arthritis Care Res (Hoboken). https://doi.org/10.1002/acr.23769

28.

Winthrop KL, Wouters AG, Choy EH, Soma K, Hodge JA, Nduaka CI, Biswas P, Needle E, Passador S, Mojcik CF, Rigby WF (2017) The safety and immunogenicity of live zoster vaccination in patients with rheumatoid arthritis before starting tofacitinib: a randomized phase II trial. Arthritis Rheumatol 69(10):1969–1977. https://doi.org/10.1002/art.40187 CrossRefPubMedPubMedCentral

29.

Weyand CM, Fujii H, Shao L, Goronzy JJ (2009) Rejuvenating the immune system in rheumatoid arthritis. Nat Rev Rheumatol 5(10):583–588. https://doi.org/10.1038/nrrheum.2009.180 CrossRefPubMed

30.

Weyand CM, Goronzy JJ (2016) Aging of the immune system. Mechanisms and therapeutic targets. Ann Am Thorac Soc 13(Supplement_5):S422–S428. https://doi.org/10.1513/AnnalsATS.201602-095AW CrossRefPubMedPubMedCentral

31.

Goronzy JJ, Shao L, Weyand CM (2010) Immune aging and rheumatoid arthritis. Rheum Dis Clin N Am 36(2):297–310. https://doi.org/10.1016/j.rdc.2010.03.001 CrossRef

32.

Krasselt ML, Wagner U (2014) Ageing and immunity. Osteology 23(3):195–201CrossRef

33.

Krasselt M, Baerwald C, Wagner U, Rossol M (2013) CD56+ monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and immunosenescence. Arthritis Res Ther 15(5):R139. https://doi.org/10.1186/ar4321 CrossRefPubMedPubMedCentral

34.

Crowson CS, Liang KP, Therneau TM, Kremers HM, Gabriel SE (2010) Could accelerated aging explain the excess mortality in patients with seropositive rheumatoid arthritis? Arthritis Rheum 62(2):378–382. https://doi.org/10.1002/art.27194 CrossRefPubMedPubMedCentral

35.

Weyand CM, Brandes JC, Schmidt D, Fulbright JW, Goronzy JJ (1998) Functional properties of CD4+ CD28- T cells in the aging immune system. Mech Ageing Dev 102(2–3):131–147CrossRefPubMed

36.

Ventura MT, Casciaro M, Gangemi S, Buquicchio R (2017) Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin Mol Allergy 15:21. https://doi.org/10.1186/s12948-017-0077-0 CrossRefPubMedPubMedCentral

37.

Buffa S, Bulati M, Pellicano M, Dunn-Walters DK, Wu YC, Candore G et al (2011) B cell immunosenescence: different features of naive and memory B cells in elderly. Biogerontology 12(5):473–483. https://doi.org/10.1007/s10522-011-9353-4 CrossRefPubMed

38.

Chalan P, van den Berg A, Kroesen BJ, Brouwer L, Boots A (2015) Rheumatoid arthritis, immunosenescence and the hallmarks of aging. Curr Aging Sci 8(2):131–146CrossRefPubMedPubMedCentral

39.

Petersen LE, Grassi-Oliveira R, Siara T, dos Santos SG, Ilha M, de Nardi T et al (2015) Premature immunosenescence is associated with memory dysfunction in rheumatoid arthritis. Neuroimmunomodulation 22(3):130–137. https://doi.org/10.1159/000358437 CrossRefPubMed

40.

van der Geest KS, Abdulahad WH, Chalan P, Rutgers A, Horst G, Huitema MG et al (2014) Disturbed B cell homeostasis in newly diagnosed giant cell arteritis and polymyalgia rheumatica. Arthritis Rheumatol 66(7):1927–1938. https://doi.org/10.1002/art.38625 CrossRefPubMed

41.

Pritz T, Lair J, Ban M, Keller M, Weinberger B, Krismer M, Grubeck-Loebenstein B (2015) Plasma cell numbers decrease in bone marrow of old patients. Eur J Immunol 45(3):738–746. https://doi.org/10.1002/eji.201444878 CrossRefPubMed

42.

Zharhary D, Klinman NR (1983) Antigen responsiveness of the mature and generative B cell populations of aged mice. J Exp Med 157(4):1300–1308CrossRefPubMed

43.

Goidl EA, Innes JB, Weksler ME (1976) Immunological studies of aging. II. Loss of IgG and high avidity plaque-forming cells and increased suppressor cell activity in aging mice. J Exp Med 144(4):1037–1048CrossRefPubMed

44.

Buffa S, Pellicano M, Bulati M, Martorana A, Goldeck D, Caruso C et al (2013) A novel B cell population revealed by a CD38/CD24 gating strategy: CD38(−)CD24 (−) B cells in centenarian offspring and elderly people. Age (Dordr) 35(5):2009–2024. https://doi.org/10.1007/s11357-012-9488-5 CrossRef

45.

Sherina N, Hreggvidsdottir HS, Bengtsson C, Hansson M, Israelsson L, Alfredsson L, Lundberg K (2017) Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology. Arthritis Res Ther 19(1):219. https://doi.org/10.1186/s13075-017-1423-9 CrossRefPubMedPubMedCentral

46.

Elkayam O, Paran D, Caspi D, Litinsky I, Yaron M, Charboneau D, Rubins JB (2002) Immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus. Clin Infect Dis 34(2):147–153. https://doi.org/10.1086/338043 CrossRefPubMed

47.

Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C et al (2010) Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum 62(1):64–74. https://doi.org/10.1002/art.25034 CrossRefPubMed

48.

Kapetanovic MC, Saxne T, Sjoholm A, Truedsson L, Jonsson G, Geborek P (2006) Influence of methotrexate, TNF blockers and prednisolone on antibody responses to pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis. Rheumatology (Oxford) 45(1):106–111. https://doi.org/10.1093/rheumatology/kei193 CrossRef

49.

Fomin I, Caspi D, Levy V, Varsano N, Shalev Y, Paran D et al (2006) Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers. Ann Rheum Dis 65(2):191–194. https://doi.org/10.1136/ard.2005.036434 CrossRefPubMed

50.

Oren S, Mandelboim M, Braun-Moscovici Y, Paran D, Ablin J, Litinsky I, Comaneshter D, Levartovsky D, Mendelson E, Azar R, Wigler I, Balbir-Gurman A, Caspi D, Elkayam O (2008) Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response. Ann Rheum Dis 67(7):937–941. https://doi.org/10.1136/ard.2007.077461 CrossRefPubMed

51.

Koh JH, Lee J, Kim SH, Kwok SK, Ju JH, Park SH (2018) Safety, and humoral and cell-mediated immune responses to herpes zoster vaccine in patients with rheumatoid arthritis. J Rheumatol 45(4):465–469. https://doi.org/10.3899/jrheum.170936 CrossRefPubMed

52.

Yawn BP, Gilden D (2013) The global epidemiology of herpes zoster. Neurology 81(10):928–930. https://doi.org/10.1212/WNL.0b013e3182a3516e CrossRefPubMedPubMedCentral

Title: Humoral immunity to varicella zoster virus is altered in patients with rheumatoid arthritis
Authors: Marco Krasselt
Christoph Baerwald
Uwe G. Liebert
Olga Seifert
Publication date: 01-09-2019
Publisher: Springer London
Keywords: Shingles
Human Alphaherpesvirus 3
Vaccination
Disease Modifying Anti-Rheumatic Drug
Rheumatoid Arthritis
Published in: Clinical Rheumatology / Issue 9/2019
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-019-04563-9

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Humoral immunity to varicella zoster virus is altered in patients with rheumatoid arthritis

Abstract

Introduction

Methods

Results

Conclusions

Key Points

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusions

Key Points

Please log in to get access to this content

Other articles of this Issue 9/2019

Correction to: Gout and healthcare utilization and complications after hip arthroplasty: a cohort study using the US National Inpatient Sample (NIS)

Correction to: Behçet’s disease in Egypt: a multicenter nationwide study on 1526 adult patients and review of the literature

Association of cumulative anti-cyclic citrullinated protein antibodies with radiographic progression in patients with rheumatoid arthritis

Pan-American League of Associations for Rheumatology (PANLAR) capillaroscopy study group consensus for the format and content of the report in capillaroscopy in rheumatology

Concomitant methotrexate has little effect on clinical outcomes of abatacept in rheumatoid arthritis: a propensity score matching analysis

Clinical characteristics of Polish patients with ANCA-associated vasculitides—retrospective analysis of POLVAS registry

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page