Eleftheriou, D

Maritsi, DN

Onoufriou, M

Vartzelis, G

UCL Discovery

TITLE PAGE     Decreased antibodies against Hepatitis A in previously vaccinated treatment naïve jSLE patients: a prospective case control study  Despoina N. Maritsi1,2, Margarita Onoufriou2, George Vartzelis1 ……..  1. Second Department of Pediatrics, ”P. & A. Kyriakou” Children’s Hospital, Medical Faculty, University of Athens, Greece  2. “Makarios III” Children’s’ Hospital, Nicosia, Cyprus  Corresponding author: Despoina N. Maritsi, MD, MSc, PhD, MRCPCH Second Department of Paediatrics, “P. & A. Kyriakou” Children’s Hospital, Medical Faculty, University of Athens, Greece Email: dmaritsi@gmail.com, tel: +302130051684, fax: +302118007798   Type of article: Letter      Key words: Inactivated Hepatitis A vaccine Juvenile SLE Immune status Immunosuppressive treatment        Sir,  Juvenile SLE (jSLE) patients are susceptible to infections due to their defective immune system and the immunosuppressive treatment they receive [1]. However we lack data regarding reponse to certain vaccine preventable diseases. Hepatitis A is an indolent disease with a varying clinical spectrum and consequences and also a vaccine avoidable disease with intermediate endimicity in Mediterranean countries [2].  In this study we aimed to define the immune status against Hepatitis A virus (HAV) in previously vaccinated jSLE patients, prior to commencement of treatment and at one and three years, and compare this to healthy controls. This was a prospective matched controlled study including 21 newly diagnosed jSLE patients and 76 healthy controls. The control group consisted of healthy children matched for ethnic origin, age and gender to the control group, attending the Pediatric Outpatients Department for routine checks; the same exclusion criteria applied. All participants had two doses of the inactivated Hepatitis A vaccine in early childhood. Exclusion criteria were underlying immunodeficiency, recent blood transfusion (<6 months) and previous treatment with immunomodulating agents. Demographic, clinical and laboratory data as well as data regarding immunization status, vaccine history and mean time between the doses of the vaccine were collected. Seroprotection rates and anti-HAV-IgG titers were measured at enrollment and at timely intervals afterwards (0,12,36 months). Total IgG levels were measured simultaneously. HAV-IgG antibodies were assessed by ELISA. The cutoff value for seroprotection was deemed at 20IU/ml [3]. The Hospital’s Research and Ethics’ Committee approved the study; written informed consent was obtained. Statistical significance was set at p<0.05 and analyses were conducted using SPSS (version 19.0). The two groups had similar demographic characteristics, vaccination history and immunization status. No significant differences were detected in terms of vaccine type, time interval between the two groups as well as mean time from last vaccination to blood sampling. Seroprotection rates were adequate for both groups. Nonetheless, the jSLE group had consistently inferior (but not statistically meaningful) seroprotection rates at all time-points. Mean anti-HAV IgG antibodies were significantly lower in the SLE compared to the control group (p<0.01). Similar results were found at one and three years’ follow up (table 1). None of the participants had hypogamaglobulinaemia at the time of blood sampling. During the follow up period the jSLE group had greater decrease in antibody levels as indicated from the significant interaction effect of analysis. There was no association detected between degree of antibody loss and type of treatment or jSLE disease activity. This was a novel study concerning antibody status against Hepatitis A in children with jSLE. Fully vaccinated participants showed satisfactory seroprotection rates and antibody titers. Nonetheless, we detected increased antibody loss against Hepatitis A in children with jSLE, which further accelerated once treatment is initiated. Low antibody titers could be attributed to the disease[4], its activity[5] or medications[6]. Studies concerning other vaccines, performed in children with IBD, JIA and jSLE showed matching results[7,8,9]. The majority of patients with jSLE receive long-term immunosuppressive treatment. B cell depletion observed in patients under immunosuppressive treatment is a well-documented factor leading to antibody depletion; hence the accelerated rate of antibody loss can be justified. Immunity against certain viruses is severely affected in patients receiving immunosuppressive treatment, rendering these patients susceptible to HAV infection[10]. In fact, corticosteroids and immunosuppressants are associated with decreased vaccine serological response whereas hydroxicloroquine seems to improve vaccine immunogenicity[4]. Additionally, steroid use seems to hamper immunogenicity in a dose dependent manner[6].  SLE is partially a lymphocyte-mediated autoimmune disease with abnormality in the adaptive immune system. Self-antigens set off reactive T cells including Th1 cells with production of pro-inflammatory cytokines. Defective Th1 reaction has been repeatedly reported in vaccine non-responders, rendering this hypothesis challenging for further insight[11]. Our study was underpowered to bring up differences amongst the different treatment groups and correlate disease activity to antibody loss. Finally, although baseline immunology tests were carried out, further studies on B cell function were not performed. In conclusion, although seroprotection rates were similar between the two groups, mean anti-HAV-IgG titers were significantly lower in the jSLE group at all time-points. Further studies are required to address the question of long-term immunity conveyed by immunizations given at an early stage in children with rheumatic diseases. However, evaluation of immunization status against all vaccine preventable diseases in such patients may be beneficiary.       Key messages:   Children with autoimmune diseases show evidence of immune dysregulation.   Accelerated antibody loss against Hepatitis A is noted in children with jSLE                                        Table 1: Demographic characteristics, seroprotection rates and mean anti-HAV IgG titers for the SLE and the control group  Parameters SLE group Control group P value   P-value: * Student t-test, +Pearson’s chi-square test     Acknowledgements: The authors wish to thank the families for their participation and support  Conflict of interest: None  Study sample, n 21 76 0.9* Age, years, mean (SD) 11.3 (2.3) 10 (2.7) 0.8* Gender n (%) female male    20 (95%)   1 (5%)  72 (95%)   4 (5%)  0.83+ Fully vaccinated Partially vaccinated (other than HAV)  16 (71%)  5 (29%)  62 (83%) 14 (17%) 0.4+  Type of vaccine given  HAVRIX  VAQTA   34 (81%)   8 (19%)  119 (78%)  33 (22%)  0.84+  Mean interval between  doses (months)  19  23 0.3* Mean time from last dose to sampling (years)  6  5.4  0.7* Steroids (21/21)  mean dose  mean duration of treatment HCQ (21/21)  mean dose  mean duration of treatment Azathioprine (9/21)  mean dose   mean duration of treatment  SLEDAI score  Enrolment  1 year  3 years  10mg 17 months  200mg 36 months  75mg 18 months   7 1 0  NA   - Seroprotection rate at diagnosis (%) 95 98 0.4+ Seroprotection rate at 1 years(%) 92 97 0.1+ Seroprotection rate at 3 years (%) 89 96 0.06+ Mean IgG titers at diagnosis, mIU/ml 167 249 < 0.01* Mean IgG titers at 1 year, mIU/ml 131 218  < 0.01*  Mean IgG titers at 3 years, mIU/ml 134 202 < 0.01* Source of funding: None required   REFERENCES: 1. Atzeni F, Bendtzen K, Bobbio-Pallavicini F, Conti F, Cutolo M, Montecucco C,et al. Infections and treatment of patients with rheumatic diseases. Clin Exp Rheumatol. 2008;48:S67–73.  2. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization recommendations of the Advisory Committee on Immunization Practice(ACIP). MMWR Recommend Rep. 2006;55:1–23 3.  Karpinski KF, Hayward S, Tryphonas H. Statistical considerations in the quantitation of serum immunoglobulin levels using the enzyme-linked immunosorbent assay(ELISA).J Immunol Methods1987;103:189-94 4. Pasoto SG, Ribeiro AC, Bonfa E. Update on infections and vaccinations in systemic lupus erythematosus and Sjögren's syndrome. Curr Opin Rheumatol. 2014;26:528-37. 5. Campos LM, Silva CA, Aikawa NE, Jesus AA, Moraes JC, Miraglia J, Ishida MA, Bueno C, Pereira RM, Bonfa E. High disease activity: an independent factor for reduced immunogenicity of the pandemic influenza a vaccine in patients with juvenile systemic lupus erythematosus. Arthritis Care Res. 2013;65:1121-7 6. Aikawa NE, Campos LM, Silva CA, Carvalho JF, Saad CG, Trudes G, Duarte A, Miraglia JL, Timenetsky Mdo C, Viana VS, França IL, Bonfa E, Pereira RM Glucocorticoid: major factor for reduced immunogenicity of 2009 influenza A (H1N1) vaccine in patients with juvenile autoimmune rheumatic disease. J Rheumatol. 2012;39:167-73.  7. Maritsi D, Vartzelis G, Soldatou A, Garoufi A, Spyridis N. Markedly decreased antibody titers against hepatitis B in previously immunized children presenting with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2013; 31: 969-73  8. Radzikowski A, Banaszkiewicz A, Łazowska-Przeorek I, Grzybowska-Chlebowczyk U, Woś H, Pytrus T, Iwańczak B, Kowalska-Duplaga K, Fyderek K, Gawrońska A, Karolewska-Bochenek K, Kotowska M, Albrecht P. Immunogenicity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17: 1117-24 9. Heijstek MW, Van Gageldonk PG, Ber-Bers GA et al.: Differences in persistence of measles, mumps, rubella, diphtheria and tetanus antibodies between children with rheumatic disease and healthy controls: a retrospective cross-sectional study. Ann Rheum Dis 2012; 71: 948-54. 10. Ramos-Casals M, Cuadrado MJ, Alba P, Sanna G, Brito-Zerón P, Bertolaccini L, Babini A, Moreno A, D'Cruz D, Khamashta MA. Acute viral infections in patients with systemic lupus erythematosus: description of 23 cases and review of the literature. Medicine. 2008;87:311-8.   11. Jafarzadeh A, Shokri F: The antibody response to HBs antigen is regulated by co- ordinated Th1 and Th2 cytokine production in healthy neonates Clin Exp Immunol 2003; 131: 451-6.   

Decreased antibodies against hepatitis A in previously vaccinated treatment naïve juvenile SLE patients: a prospective case control study

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Decreased antibodies against hepatitis A in previously vaccinated treatment naïve juvenile SLE patients: a prospective case control study

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