Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by relapsing and remitting disease activity. Immunosuppressive drugs are often needed to control disease activity rendering patients more susceptible to infection. Immunocompromised patients have an increased risk of morbidity and mortality following influenza infection.¹ Thus influenza vaccination should be considered in SLE patients. It is, however, still questionable whether vaccination might induce disease activity in patients with established autoimmune disease. Limited numbers of studies have been undertaken to establish whether influenza vaccination is safe in SLE patients.^2–,⁹ These studies have their limitations, as most dealt with small numbers of patients^3,4,6,8,9 and included patients irrespective of their level of disease activity.^4,5,7–,⁹

Furthermore, it is unclear whether vaccination is effective in SLE patients, as they are assumed to have decreased primary and secondary immune responses.¹⁰ In addition, the use of immunosuppressive drugs may further decrease the immune response following vaccination. In some studies it has been shown that SLE patients have a reduced antibody response after vaccination compared with healthy adults.^4,7,11 In contrast, other studies suggested a normal vaccination efficacy.^2,3,5,6 In transplantation patients the use of drugs such as corticosteroids, azathioprine, and ciclosporine decreases the antibody response after vaccination^12–,¹⁶; however, the influence of immunosuppressive drugs on efficacy of influenza vaccination in SLE patients has not been thoroughly examined.

In this study we assessed the safety and efficacy of influenza vaccination and the effect of drugs on vaccination efficacy in an (immunosuppressed) cohort of SLE patients.

METHODS

RESULTS

Fifty six SLE patients and 18 healthy controls were studied. Forty three (77%) of the SLE patients had received influenza vaccination in the past compared with four (22%) of the healthy controls (p<0.001). Thus more patients (34 of 56) than controls (1 of 17) had received influenza vaccination the year before (2002/2003; p<0.001), which consisted of the same viral antigens. Data on the four study groups are shown in table 1⇓. Median doses for the drugs which defined the groups were 400 mg/day for hydroxychloroquine in group B, 100 mg/day for azathioprine in group C, and 10 mg/day for prednisone in group D. Baseline characteristics were equally distributed among the groups. Patient groups did not differ before vaccination for duration of SLE, patient VAS, or SLEDAI (fig 1⇓, p = 0.644). Within patient groups, the numbers of patients who had received influenza vaccination in the past were comparable (p = 0.231); however, more patients in the azathioprine group had received vaccination in the previous influenza season (2002/2003) than patients in the other groups (p = 0.026).

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Figure 1

 Influence of vaccination on disease activity in the different patient groups. Disease activity was measured by the SLE disease activity index (SLEDAI) (A) and patient visual analogue score (VAS) (B), depicting patients’ perception of disease activity. Columns are means, error bars = SEM. The left bars in each pair represent results before, the right bars 30 days after vaccination. *p<0.05 (Wilcoxon signed rank test).

DISCUSSION

Our study shows that influenza vaccination is safe in SLE patients with quiescent disease but has decreased efficacy, in particular in those taking azathioprine. It can be argued that disease activity might increase over a longer period than the follow up used in this study. However, the immune response to influenza is generated during the first weeks following vaccination. If vaccination were to enhance established autoimmunity, this would be expected to occur particularly during this early period. We therefore carried out our second assessment of disease activity four weeks after the vaccination.

We found no increase in SLE disease activity or in patient perception of disease activity, as measured by patient VAS, four weeks after the vaccination. This corresponds with previous studies,^2–,⁹ in which clinical and laboratory assessed lupus disease activity did not increase after vaccination. In one study, increased disease activity was reported, though it was infrequent and usually mild.² Another study reported one patient (of 11) with significantly more disease activity following vaccination.⁶ Although SLE patients had more systemic side effects of influenza vaccination, these were all mild. Symptoms such as tiredness, sweating, and myalgia—which were considered as side effects—are common in SLE patients, although these are not criteria for disease activity in SLEDAI. Whereas SLEDAI scores did not change, the symptoms mentioned above occurred in some patients following vaccination. This suggests at the least a temporal relation. However, the higher frequency of side effects might have been a result of a reporting bias in patients. It is known that many SLE patients with quiescent disease experience a decreased sense of wellbeing,^23–,²⁵ which contributes to such a bias. We conclude that influenza vaccination in SLE patients appears to be safe.

Studies concerning the efficacy of influenza vaccination thus far are conflicting, as some indicate normal efficacy in SLE patients^2,3,5,6 whereas others conclude that efficacy is reduced.^4,7,11 An overview is given in table 8⇓. In general, these studies contained fewer patients than our study, efficacy was partially analysed, and effects of previous vaccinations were not mentioned. In addition, the effects of differences in drug use were often not sufficiently taken into account. Furthermore, previous influenza vaccinations were not recorded. In summary, conflicting data can be explained by methodological differences.

We therefore evaluated the efficacy of influenza vaccination in SLE patients in several ways. With respect to the percentage of patients who achieved seroconversion or a fourfold titre rise we found that influenza vaccination was less effective for A/H1N1 and A/H3N2 in SLE patients. Accordingly, fewer SLE patients achieved a protective titre after vaccination against both the influenza A strains together when compared with healthy controls, despite the fact that more patients than controls had received a vaccination with the same viral antigens the year before. We suggest that the GMT in SLE patients after vaccination did not differ from the controls because GMT before vaccination was higher in the patients—which can easily be accounted for by their higher rate of previous vaccination. The conclusion that SLE patients appear to have a decreased immune response compared with healthy controls is supported by the subanalysis of those patients and controls who did not have influenza vaccination the previous season. In these subgroups there was also a significantly decreased humoral response to A/H1N1 and A/H3N2 in the SLE patients compared with the controls.

To evaluate whether our group of healthy controls was representative we compared the GMTs of this group with those of a healthy control group vaccinated in the course of a routine survey of the 2002/2003 Influvac vaccine (data kindly provided by Solvay Pharmaceuticals, Weesp, Netherlands). The 2002/2003 vaccine was identical to the 2003/2004 vaccine used in our study. A group of 17 healthy persons, age and sex matched, was compared with our group of controls. In the Solvay survey, the GMT of A/H1N1 increased from 7.5 to 221.4, of A/H3N2 from 16.0 to 247.2, and of B/Hong Kong from 8.2 to 90.0. The change in GMTs did not differ statistically from the results obtained in the controls in the present study (Mann–Whitney U test). Why patients showed a decreased humoral responses to both influenza A strains, but not to the B/Hong Kong strain is open to discussion. As the healthy controls in our study appeared to have a decreased response to the influenza B strain, a possible explanation is that the immunogenicity of the influenza B strain was lower than that of the influenza A strains included. This might have caused a smaller difference in response between patients and controls, in which case the power of our study could have been too low to detect such a difference.

It is reported that the H3N2 subtype of influenza A causes more severe illness than A/H1N1 or influenza B,²⁶ and in most seasons the prevalence of influenza A infections is higher than influenza B infections.²⁷ So sufficient protection against influenza A (especially A/H3N2) is clinically more relevant than sufficient protection against influenza B.

Why SLE patients have a decreased response to influenza vaccination is not entirely clear. Ioannou et al showed that vaccinations in SLE patients generally tend to give rise to lowered immune responses.²⁸ Another study showed that pneumococcal vaccination in SLE patients in general is immunogenic, but that a subset of patients may remain unprotected by the currently available vaccine.²⁹ It is conceivable that SLE patients have an intrinsic immunological defect that results in decreased responsiveness to vaccination. The assumption of an intrinsic immune defect is supported by studies reporting decreased cellular immune responses to influenza in SLE patients.^30,31

In addition, the use of immunosuppressive drugs may influence the efficacy of vaccination. To assess this effect, we included patients using hydroxychloroquine, azathioprine, or prednisone, and analysed data from these groups of patients separately, as there are considerable differences in pharmacological effects between these drugs. Patients using other immunosuppressive agents were excluded to prevent the formation of small heterogeneous subgroups. SLE patients receiving azathioprine showed a trend towards a decreased immune response against influenza A/H3N2 compared with the other patient groups. This is in concordance with the study of Abu-Shakra et al, in which a trend towards a decreased immune response to influenza vaccination was observed in SLE patients who received azathioprine.¹¹ In renal transplant patients the use of azathioprine was reported to lower the antibody response to influenza vaccination compared with healthy controls,³² but this could not be confirmed by others.¹⁶ Although the number of patients included in this study is quite substantial, the subgroups (according to treatment) are quite small. Data on the effects of immunosuppressive drugs on the efficacy of the vaccination should therefore be interpreted with caution.

Twenty five per cent of SLE patients achieved titres of <40 against both the influenza A strains together and are not expected to be protected from influenza A infection.²² Moreover, one might expect that SLE patients experience less protection from influenza vaccination because cellular immunity also seems to be impaired after vaccination.^30,31

To improve the antibody response of immunosuppressed patients several studies have been conducted in which a second vaccination was given. In general, in immunocompromised patients an increased antibody response could not be achieved after a booster injection,^33,34 although Soesman et al did find an increased response in liver transplant patients.¹⁵ Recent studies have shown that virosomal vaccines generate better cellular immune responses, and they enhance the humoral immune response following vaccination as well.^35–,³⁸ Regarding the hampered humoral and cellular immune response to influenza vaccination in SLE patients, these new vaccines are of particular interest as one might expect them to improve the efficacy of vaccination in SLE patients.