Why Have Rheumatologists Been Reluctant to Vaccinate Patients with Lupus?

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Editorial: Why Have Rheumatologists Been Reluctant to Vaccinate Patients

with Systemic Lupus Erythematosus?

http://www.jrheum.com/subscribers/06/08/1469.html

Patients with systemic lupus erythematosus (SLE) have multiple immunological

abnormalities, including B cell hyperactivity, hypergammaglobulinemia,

increased production of autoantibodies, and T cell dysfunction with abnormal

cytokine production 1 . It has been suggested that all these immunological

changes are due to a defect in eliminating self/reactive T cells or B cells.

Infection is a major cause of morbidity and mortality in patients with SLE,

therefore the prevention of viral and bacterial infection is very important.

Patients with lupus are prone to infections due to the immunological

abnormalities of the disorder itself or to the frequent use of

corticosteroids and/or immunosuppressive drugs. For this high-risk

population, vaccination might be useful, provided the vaccine produces

protective antibodies (for example, seroconversion or >= 4-fold rise in

titer) without inducing autoimmune disease, increasing preexisting

autoantibodies (anti-DNA, anti-Sm, anti-RNP, anti-Ro), or flaring the

underlying rheumatic disease.

In 1976, the National Influenza Immunization Program in the US caused

clinicians to reexamine the possible benefits and risks of influenza

vaccination in patients with SLE. Because viral infection has long been

postulated to play a role in autoimmune disease, rheumatologists believed

that vaccination in patients with SLE might trigger autoantibody production

or increase disease activity.

In 1978 and 1979, US researchers first reported on the safety, lack of

induction of autoimmune phenomena, and serum protective antibody

concentrations following univalent or bivalent influenza vaccination in

patients with SLE who either were in remission or had a mild to moderate

disease activity 2-6 . The serum hemagglutination-inhibiting antibody titers

to influenza antigens were measured before and 4 and 8 weeks after

vaccination. Protective antibody titers were defined as a >= 4-fold rise in

titer, although that does not give a true indication of the functional

capacity of these antibodies, particularly their opsonizing activity.

However, no validated disease activity measure was used.

At that time, the safety and immunogenicity of 14-valent pneumococcal

vaccine was also reported in a controlled trial 7 and later extended by

other investigators 8-10 . The mean antibody levels were lower at both 1

month and 1 year after vaccination in 38 patients with SLE than in healthy

controls. A study examined the persistence of pneumococcal antibodies in

19/38 patients with SLE at 1, 2, and 3 years after immunization and compared

to 5 healthy subjects vaccinated at the same time. The mean levels in the 19

patients with lupus were lower in all 3 years, but the difference was

significant at only the first year. At 3 years, only 8/19 patients had

protective antibodies. No significant changes in anti-DNA were present.

Another study demonstrated that antibody responses were unaffected by

immunosuppressive drugs.

FROM SINGLE TO MULTIPLE SIMULTANEOUS VACCINES

In 1998, Battafarano, et al 11 demonstrated the safety and efficacy of

simultaneous administration of pneumococcal, tetanus toxoid (TT), and

Haemophylus influenzae type B (HIB) vaccines in 73 consecutive patients with

lupus. Disease activity [sLE Disease Activity Index (SLEDAI) and Lupus

Activity Criteria Count (LACC)] scores were evaluated prevaccination and 12

weeks after vaccination. Most of these patients developed protective

antibody levels to at least one vaccine, disease activity was unaffected by

vaccination, and antigen-specific antibody response was lower in patients

with active disease receiving immunosuppressives, but this was not

statistically significant.

Shortly thereafter, I conducted a study involving 12 patients with lupus who

concurrently received 23-valent pneumococcal and HIB conjugate vaccines 12 .

HIB conjugate vaccine contains 20 µg of tetanus protein. All patients were

taking oral prednisone (mean 18.1 mg, range 5-50 mg per day) at the time of

vaccination. Anti-DNA antibodies, C3 complement, serum IgG levels,

Mex-SLEDAI score, and antibodies against pneumococcus and 4 serotypes as

well as HIB vaccine and tetanus protein were assessed at baseline and at 4

weeks. Significant increases occurred in antibody levels to vaccines and to

all 4 serotypes tested as well as tetanus protein after vaccination.

Decreases in Mex-SLEDAI score and serum IgG level were seen, while C3 level

increased significantly. No changes in anti-DNA antibodies were noted. The

vaccines were well tolerated, and no serious adverse events were recorded.

To further assess the persistence of antibodies against pneumococcal

vaccine, serum samples of 9 patients were obtained at 8 months; none had

protective antibodies. Other reports also confirmed the safety and

immunogenicity of polyvalent pneumococcal vaccine in patients with SLE 13-15

..

Beginning in the new century, studies related to influenza virus vaccination

in adult and child patients with SLE appeared 16-18 . In the first study,

Abu-Shakra and coworkers 16 showed the safety of vaccination in 24 patients

using SLEDAI scores, and recommended that patients with lupus should be

encouraged to receive the vaccine. In December 2002, Abu-Shakra, et al 17

showed that specific antibody response was lower than in adults in the

general population, in particular among older patients and those treated

with cytotoxic drugs. In the third study, Abu-Shakra, et al 18 examined

effects on generation of autoantibodies following influenza vaccination.

They found that influenza vaccination may trigger the generation of

autoantibodies, although this was not clinically significant.

In the fourth study, Greek researchers 19 showed that influenza vaccine

generated a good antibody response in children with lupus, as in control

children. The response was not affected by the use of immunosuppressive

therapy. No increase in autoantibody production or disease flare was seen.

Finally, in the fifth paper on the subject, my colleagues and I 20 showed

that influenza vaccination in patients with SLE was safe, there was a

significant increase in antibody responses, patients developed protective

antibodies despite immunosuppressive therapy and disease activity, anti-DNA

antibodies did not change after vaccination, and induction and/or increase

of autoantibodies was not constant and was not clinically significant. To

further evaluate the duration of vaccine-induced antibody, serum samples of

7 patients who had completed 12 months after vaccination were taken. Six out

of 7 had protective titers for all 3 influenza antigens, and one more

patient had protective titers to only 2 antigens.

HEPATITIS B VACCINE AND SLE

Over the past few years, autoimmune hazards of hepatitis B (HB) vaccination

have been described in the literature. Whether autoimmune manifestations are

consequence or coincidence after administration of viral vaccines remains

controversial. A recent extensive literature review 21 showed (1) biologic

plausibility of a relationship between HB surface antigen and SLE was

unlikely; (2) case reports or series of patients who developed lupus after

vaccination were rare and not convincing regarding potential causality; and

(3) there were neither controlled observational studies nor controlled

clinical studies. Therefore, the decision to vaccinate a patient with an

immunological disorder should rely, not on case reports, but on evidence

based medicine.

CONCLUSION

The safety and immunogenicity of vaccine against pneumococcus and influenza

virus, first reported in the late 1970s, have now been confirmed. There is

no evidence of exacerbation of disease. Patients with SLE develop protective

antibodies despite disease activity and immunosuppressive drugs.

Interestingly, the humoral immune response to these vaccines is

antigen-specific and independent of the production of anti-DNA antibodies,

and the induction of autoimmune phenomena is an uncommon occurrence.

Because the prevention of microbial infection, which is a leading cause of

morbidity in patients with SLE, is very important, they should receive these

vaccines even though antibody levels may be lower than those of healthy

controls. Therefore, it seems prudent to continue to monitor antibody

titers. I believe that the measurement of antibody levels should be once a

year, and patients may need revaccination against pneumococcus earlier than

the recommended 5 years.

ULISES MERCADO, MD, MSc, FACR, Professor of Medicine,

Hospital General de Mexicali and Universidad Autonoma de Baja California,

Mexicali, Mexico

Address reprint requests to Dr. U. Mercado, 337 First Street, MSC 20765,

Calexico, CA 92231, USA. E-mail: ulisesmercado@...