Influenza vaccination of patients with systemic lupus erythematosus

Vacunación contra virus de la influenza
en pacientes con lupus eritematoso sistémico

Ulises Mercado
Héctor Acosta
Leonel Avendaño
Hospital General de Mexicali, ISESALUD y Universidad Autónoma de Baja California, Mexicali, México

Correspondence and reprint request:

Ulises Mercado, MD
Hospital General de México, ISESALUD y
Universidad Autónoma
de Baja California, Mexicali, México
Tel. 554-6825, 554-8727
Tel.y Fax 554-9362

Recibido el 12 de abril de 2003
Aceptado el 26 de agosto de 2003

ABSTRACT

Objective. To determine the safety, the immunogenicity, and the increase of pre-existing autoantibodies in patients with systemic lupus erythematosus (SLE) following influenza vaccination. Patients and Methods. Eighteen women with SLE received an inactivated influenza vaccine. Antibody titers were measured before and 4 weeks after vaccination using a standardized hemagglutination inhibition (HAI) assay. Disease activity and antinuclear autoantibodies were determined at study entry, at 4 weeks, and at 8 weeks after vaccination. Results. After vaccination, the percentage of patients with anti-hemagglutinin antibody levels increased significantly but was lower than in healthy women. Mean antibody titer of patients increased significantly but also was lower than that of controls. Both the mean of disease activity and anti-ds DNA antibody decreased significantly. Adverse effects to the vaccine were mild. Conclusions. a) Influenza vaccination appears to be safe; b). Antibody response to influenza vaccination increases significantly for all 3 influenza antigens; c) Specific antibody response is not significantly affected by treatment, age, IgG levels, or disease activity.

KEY WORDS. Influenza vaccination. Systemic lupus erythematosus. Hemagglutination inhibition assay. Antinuclear autoantibodies. Antibody response.

RESUMEN

Objetivo. Determinar la seguridad, la respuesta de anticuerpo y el aumento de autoanticuerpos preexistentes en pacientes con lupus después de la vacunación contra influenza. Métodos. Dieciocho mujeres con LES recibieron vacuna contra influenza inactivada. Se determinaron los títulos de anticuerpos antiinfluenza (prueba de inhibición de la hemaglutinación) antes y a las cuatro semanas después de la vacunación. Antes, a las cuatro y ocho semanas se midieron la actividad de la enfermedad y autoanticuerpos antinucleares. Resultados. Después de la vacunación, el porcentaje de pacientes con LES con títulos de anticuerpos antihemaglutinina aumentaron significativamente pero fueron bajos comparado con las mujeres sanas. La media de títulos de anticuerpos antiinfluenza aumentó significativamente a las cuatro semanas, pero fue más bajo que en los controles. La media de la actividad de la enfermedad y de anticuerpos antiDNA disminuyó significativamente. Los efectos colaterales fueron leves. Conclusiones. a) La vacuna contra influenza es segura; b) La respuesta de anticuerpos después de la vacunación aumenta significativamente; c) No hay correlación significativa entre la respuesta de anticuerpo con la edad, tratamiento, niveles de IgG o con la actividad de la enfermedad

PALABRAS CLAVE. Vacunación. Influenza. Lupus. Autoanticuerpos. Inhibición de la hemaglutinación. Respuesta de anticuerpo.

Patients with systemic lupus erythematosus (SLE) have a high risk for influenza infections, particularly if they are on immunosuppressive therapy. Vaccination against influenza functions primarily by inducing hemagglutination-inhibition (HAI) antibodies, which block the viral hemagglutinin, responsible for attachment to and entry into host cells. In early studies, ^1-6 influenza virus vaccine was generally well tolerated and generated high levels of antibodies against influenza antigens. A relative lack of induction of autoantibodies after vaccination was also observed. ^3,6 Most recently Abu-Shakra, et al. ⁷ reported the antibody response to trivalent influenza virus vaccine in 24 SLE patients. They found that the specific antibody response to influenza antigens is lower than that seen in adults in the general population, in particular among older patients and those treated with immunosuppressive drugs. In this study we investigated the safety, the immunogenicity, and the generation or the increase of pre-existing autoantibodies in patients with SLE after influenza virus vaccination.

MATERIALS AND METHODS

Patients and follow-up

Between October 2001 and May 2002, 18 SLE patients received an influenza virus vaccine at the Hospital General de Mexicali, ISESALUD, Baja California, Mexico. All study subjects provided oral informed consent before being enrolled. All patients were women with a mean age of 34.7 years and a medium duration of disease of 8.4 years. All patients met the American College of Rheumatology classification criteria for SLE . At the time of vaccination, 17/18 patients were taking oral prednisone (mean 14.02 mg/day, range 2.5-50 mg/day). Two patients were taking oral prednisone and intravenous cyclophosphamide (glomerulonephritis), one patient was receiving ambulatory peritoneal dialysis and one other hemodialysis (oral prednisone 5 mg/day). Two patients had hemolytic anemia; one of them was taking oral prednisone and danazol, and the another one oral prednisone and antimalarial drug. One patient had pancytopenia and arthralgia and was receiving oral prednisone and NSAID. Eleven patients had active disease with either arthritis, alopecia, oral ulcers, leukopenia, lymphopenia, and thrombocytopenia, or both. These patients were receiving oral prednisone and NSAIDs or antimalarial drug. The mean Mex-SLEDAI score ⁸ was 5.5 , and anti-dsDNA antibodies by enzyme immune assay (EIA) was 21.6 UI/mL. Six of 18 patients had anti-Ro (EIA), two anti-Sm (EIA), and seven anti-RNP (EIA) antibodies.

Vaccination

Fluarix (SmithKline Beecham, Mexico), is an inactivated influenza vaccine, containing the following types and subtypes antigens: A/Moskow/10/99 (H3N2)-like strain [variant A/ Panama /2007/99]; A/New Caledonia/20/99 (H1N1); and B/Sichuan/379/99-like strain [variant B/Johannesburg /5/99]. This vaccine complies with the WHO recommended strains for the season 2001-2002. Each 0.5 mL vaccine dose contains 15 μg hemagglutinin of each of the recommended strains. Influenza vaccine was injected into the deltoid muscle. Participants were monitored for 48 h after vaccination to determine local and systemic reactions.

Antibody titers to the 3 viruses strains (American type Culture Collection, ATCC) were measured by a standardized HAI assay using human red cells group 0, Rh negative. Four hemagglutinin units of each of the influenza antigens were added to serial dilutions of the sera (1:10 to 1:80). HAI titers were expressed as the reciprocal of the maximal dilution that resulted in complete HAI. Patients were evaluated prior to and 4 weeks after vaccination. Normal immune response was defined as ≥ 4-fold a rise in HAI test 4 weeks after vaccination. Post-vaccination HAI titer ≥ 1:40 in the serum were considered protective. Geometric mean titer (GMT) of HAI antibodies was calculated to assess the immunity of the whole group. GMT of HAI antibodies in 18 healthy women with mean age of 31.0 years (range 20-54) were also measured.

Autoimmune phenomena

To assess if influenza vaccination induces antinuclear autoantibodies or increases pre-existing autoantibodies, we measured four antinuclear autoantibodies (anti-dsDNA, anti-Sm, Anti-Ro, and anti-RNP antibodies) before, at 4 weeks, and at 8 weeks after vaccination

Disease activity

The Mex-SLEDAI scores were determined at study entry, at 4 weeks, and at 8 weeks after vaccination. Immunoglobulin G (IgG) levels by radial diffusion were determined in only 10 patients with SLE at the time of vaccination.

Statistical analysis

RESULTS

Antibody response and follow-up. Before vaccination, the prevalence of serum HAI antibodies to the 3 viruses strains was lower in patients with SLE than in healthy donors. Five (28%) subjects with SLE had protective titers (≥ 1:40) to influenza A/ Moskow, four (22%) to influenza A/New Caledonia, and three (17%) to influenza B/Sichuan compared with 94% , 77%, and 94% of healthy women, respectively (Table 1). After vaccination, GMT of HAI antibodies increased significantly for all 3 viruses (Table 2). Eight patients with SLE developed HAI titers ≥ 1:40 for all 3 influenza antigens, five to 2 antigens, and two to 1 antigen. Three patients achieved ≤ 2-fold titer in rise . One of them is receiving ambulatory peritoneal dialysis, and two more are taking low-dose prednisone (2.5-7.5 mg/d). From seven patients with SLE who completed 12 months after vaccination, six had protective titers (≥ 1:40) for all 3 antigens and one more patient to only 2 antigens. Disease activity and anti-dsDNA antibody. The Mex-SLEDAI scores decreased significantly (p = 0.02), while no changes produced in anti-dsDNA antibodies levels (p = 0.97) were observed (Table 3 ).Prior to vaccination, six patients had anti-Ro, two anti-Sm, and seven had anti-RNP antibodies. At 4 weeks anti-Ro decreased to four, anti-Sm increased to five, anti-RNP decreased to four and were unchanged in eight. No clinical features were accompanied. Eight weeks after, anti-Ro and anti-RNP antibodies remained similar, and only three had anti-Sm. All 10 patients with SLE in whom IgG levels were measured had normal values (mean 1201.2 mg/mL, range 813-1783). There was not a significant correlation between antibody response to A/ Moskow, (r = 0.14, p = 0.06), A/New Caledonia (r = 0.34, p = 0.16), and B/Sichuan (r = 0.34, p = 0.17) with age; prednisone treatment (r = 0.18, p = 0.46, r = 0.16, p = 0.52, and r = -0.14, p = 0.55, respectively); disease activity, (r = -0.25, p = 0.29, r = -0.42, p = 0.07, and r = -0.18, p = 0.45, respectively); and IgG levels (r = 0.02, p = 0.94, r = -0.27, p = 0.44, and r = -0.09, p = 0.79, respectively). With regard to adverse effects, one patient reported flu-like symptoms and one more had pain at injection site. No cases of pneumonia nor hospitalization were present during the follow-up.

DISCUSSION

Despite the likelihood of increased morbidity from influenza virus infections in SLE, clinicians think that immunization may trigger SLE. However, a number of investigators have shown that influenza virus and pneumococcal vaccines are safe and effective. Besides, the simultaneous administration of pneumococcal, Hemophilus influenzae type B (HIB), and tetanus toxoid vaccines ⁹ is also safe and immunogenic in SLE patients. Previously we demonstrated ¹⁰ that the simultaneous administration of both pneumococcal and HIB vaccines are safe. The vaccine immunization was not associated with exacerbation of SLE . No significant changes in anti-dsDNA antibodies nor increased serum IgG levels after vaccination were present. The mean antibody titer for all antigens tested, including capsular serotypes and tetanus protein conjugate to HIB increased significantly. However, the persistence in the protective antibody titer (≥ 1:40) was short-lived. Here we demonstrated that the percentage of SLE patients with protective antibody titers is lower than that found in healthy blood donor women. One possible explanation for it might be that the healthy controls had recent ambiental exposure to influenza antigens. However, after influenza vaccination, GMT of HAI antibody increased significantly for all 3 influenza antigens. Forty four percent of our patients achieved protective antibodies to all 3 influenza viruses, including one patient who was receiving cyclophosphamide boluses. The another one who also was on cyclophosphamide therapy developed protective antibody titers only to influenza A antigens. Antibody response in our SLE patients was antigen specific-and was not accompanied with significant changes in anti-dsDNA levels at 4 and 8 weeks. This suggests that the production of anti-dsDNA antibody by hyperactive B cells is an independent response. We also analyzed, using Pearson's correlation, the correlation between antibody response to influenza antigens and age, glucocorticoid treatment, the Mex-SLEDAI score, and serum IgG levels. We did not find any significant correlation, possibly because of the small sample size. Recently Abu-Shakra, et al. ⁷ reported the efficacy of influenza vaccination in their 24 SLE patients. They also found a normal immune response, although they noted that there was a trend towards a lower immune response in patients with age > 50, prednisone dosage >10 mg daily and the use of azathioprine. Seven of our patients who completed 12 months after influenza vaccination had persistence of protective antibodies; one of them was receiving azathioprine, following the administration of bolus cyclophosphamide . Only one of the antinuclear autoantibodies increased transiently after vaccination without clinical manifestations. It is in agreement with previous observations that the development of such antibodies in SLE is not a constant phenomena. Our two SLE patients with chronic renal failure also developed antibody response. The patient under hemodialysis achieved protective antibodies for all 3 influenza virus, while another one under peritoneal dialysis only had a two fold titer in rise. Our work confirms earlier reports that influenza virus vaccination is generally safe. The mean Mex-SLEDAI scores at 8 weeks after vaccination was 2.8 ± l.9 compared with 5.6 ± 4.5 at the time of vaccination. One possible explanation for this decrease might be that patients with a more active disea-se were taking aggressive therapy. In summary, we observed that: a) Administration of influenza vaccine in SLE patients is safe; b) Pre-vaccination protective antibody titers are low; c) SLE patients develop protective antibodies despite immunosuppressive therapy and disease activity; d) Anti-dsDNA levels do not change after immunization; and c) it appears that the induction of autoimmune phenomena after vaccination is not a constant occurrence.

ACKNOWLEDGMENTS

This study was supported by the Universidad Autónoma de Baja California, Mexicali, Mexico as part of a project on Influenza Vaccination in Systemic Lupus erythematosus

REFERENCES

1. Williams GW, Steinberg AD, Reinertsen JL, et al. Influenza immunization in systemic lupus erythematosus. Ann Intern Med 1978; 88: 729-34.         [ Links ]

2. Ristow SC, Douglas RG, Condemi JJ. Influenza vaccination of patients with systemic lupus erythematosus. Ann Intern Med 1978; 88: 786-9.         [ Links ]

3. Brodman R, Gilfillan R, Glass D, et al. Influenza vaccine response in systemic lupus erythematosus. Ann Intern Med 1978; 88: 735-40.         [ Links ]

4. Louie JS, Nies KM, Shoji KT et al. Clinical and antibody responses after influenza immunization in SLE. Ann Intern Med 1978; 88: 790-2.         [ Links ]

5. Abu-Shakra M, Zalmanson S, Neumann L, et al. Influenza virus vaccination of patients with systemic lupus erythematosus: Effects on disease activity. J Rheumatology 2000; 27: 1681-5.         [ Links ]

6. Ranakoudi-Tsakalidou F, Trachana M, Pratsidou-Gertsi P, et al. Influenza vaccination in children with chronic rheumatic diseases and long-term immunosuppressive therapy. Clin Exp Rheumatol 2001; 19: 589-94.         [ Links ]

7. Abu-Shakra M, Press J, Varsano N, et al. Specific antibody response after influenza immunization in systemic lupus erythematosus. J Rheumatol 2002; 29: 2555-7.         [ Links ]

8. Guzman J, Cardiel MH, Arce-Salinas A, et al. Measure of disease activity in systemic lupus erythematosus. Prospective validation of 3 clinical indices . J Rheumatol 1992; 19: 1551-8.         [ Links ]

9. Batafarano DF, Battafarano NJ, Larsen L, et al. Antigen-specific antibody responses in lupus patients following immunization. Arthritis Rheum 1998; 41: 1828-34.         [ Links ]

10. Mercado U, Acosta H, Estrada J, Avendaño L. Antibody responses following vaccination in lupus patients. Rev Invest Clin 2003; 55: 93-4.         [ Links ] ]]> 1 1978 88 88 729-34 2 1978 88 88 786-9 3 1978 88 88 735-40 4 1978 88 88 790-2 5 2000 27 27 1681-5 6 2001 19 19 589-94 7 2002 29 29 2555-7 8 1992 19 19 1551-8 9 1998 41 41 1828-34 10 2003 55 55 93-4