11/5/2011. Disclosure. Background. Background. Method - Patients. Objective

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Meliha C Kapetanovic1, Tore Saxne1, Göran Jönsson2,

Lennart Truedsson3, Pierre Geborek1

The persistence of antibodies 1.5 years after

vaccination using 7-valent pneumococcal

conjugate vaccine in patients with established

rheumatoid arthritis and spondylarthropathy

Department of Clinical Sciences 1 Section of Rheumatology 2 Section of Infectious Diseases 3 Department of Laboratory Medicine, Section of Microbiology and Immunology, Lund University, Lund, Sweden

Disclosure

• Prevenar® vaccine for this study was provided by

Wyeth Pharmaceuticals

• The authors declare no conflict of interest

Background

• In middle-aged and elderly people

– both primary vaccination and revaccination with pneumococcal vaccine induce antibody responses that persist for 5 years

(Musher D M et al. J Infect Dis. 2010)

• In patients with SLE

– antibody levels were lower compared to healthy controls at years 1, 2 and 3 - at year 3, 43% of SLE patients had protective antibody levels (McDonald et al. J Rheumatol. 1984 )

• In renal transplant recipients

– vaccine responses declined by 3 years and conjugate vaccine did not improve the durability of response (Kumar D et al. Am J

transplant 2007)

Background

• the presence of putative protective antibody levels are

surrogate markers of vaccination efficacy

• the persistence of the protective antibodies is an

indicator of remaining protection against infection

(Plotkin SA. Clin. Vaccine Immunol. 2010)

• antibody levels ≥ 1 mg/L are considered protective

(Mäkelä PH et al. J. Infect. Dis. 1977)

Objective

• To study the persistence of antibodies 1.5 years

after vaccination using 7-valent pneumococcal

conjugate vaccine in patients with established

rheumatoid arthritis (RA) and

spondylarthropathy (SpA)

Method - Patients

• 505 patients were initially vaccinated

– Kapetanovic et al, Arthritis Rheum, 2011

• data on current anti-rheumatic treatment and blood

samples were obtained from 398 (79%) subjects

after mean (SD) 1.4 (0.5) years

• anti-inflammatory treatment remained unchanged

in 302 (RA=163 and SpA=139) patients

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Method - Analyses

• antibody levels against pneumococcal serotypes 23F

and 6B were analyzed by ELISA

• concentrations are given as geometric mean levels

(GML; 95% CI)

• putative protective antibody levels defined as ≥1 mg/L

• proportion (%) of patients with protective antibody

levels for both serotypes were calculated in different

treatment groups and compared to results 4-6 weeks

after vaccination

No at vaccination RA on MTX 85 RA on anti-TNF mono 79 RA on anti-TNF + MTX 89 SpA on anti-TNF mono 83 SpA on anti-TNF + MTX 83 SpA on NSAID/ analgesics 86 No (%) of pats at 1.5 years 57 67% 50 63% 55 62% 47 47% 49 59% 42 49%

Age (mean ys) 63.5 59.9 60.1 50.3 51.6 53.1

Disease duration (mean ys)

12.6 19.8 16.6 16.8 13.1 13.6

Female 77% 90% 75% 38% 57% 48%

Demographic and treatment characteristics

Ln antibod y lev els -6 -4 -2 0 2 4 6 at vaccination at 4-6 weeks after vaccination 1.5 years follow up RA on MTX RA on anti-TNF monotherapy RA on anti-TNF + MTX SpA on anti-TNF monotherapy SpA on anti-TNF + MTX SpA on NSAID/ analgesics 23F

Results

• GML for each serotype were lower in all groups

– p-value from 0.035 to <0.001; paired sample T-test

At 1.5 years follow up

compared to 4-6 weeks after vaccination

RA on MTX RA on anti-TNF mono RA on anti-TNF +MTX SpA on anti-TNF mono SpA on anti-TNF + MTX SpA on NSAID/ Analgesics 4-6 wks after vaccination 64% 60% 54% 77% 65% 85% at 1.5 years 41% 32% 20% 60% 49% 69% Relative Ratio 1.5 ys/4-6 wks 0.64 0.54 0.37 0.77 0.75 0.81

Proportion of patients with protective

antibody levels for both 23F and 6B

Percentage of patients with protective antibody levels for

both serotypes at 4-6 weeks and 1.5 years follow up

% patients with protective antibody levels for both serotypes was lower at 1.5 years follow (p<0.001; Chi2 test)

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Results

at 1.5 years follow up

• Patients with antibodies below protective levels

– were older (p< 0.001, Mann-Whitney U test)

– had longer disease duration (p=0.045, Mann-Whitney U test)

• Frequency with protective antibody levels for both

serotypes was larger in patients < 65 years (n=219)

compared to those ≥ 65 years (n=83)

– OR 3.03 95% CI 1.73-5.32, p<0.001, Chi2 test

• compared to RA, higher proportion of SpA patients

had protective antibody levels for both serotypes

– OR 3.25 % CI 2.0-5.23), p<0.001, Chi2 test

Predictor analyses of persistence of

protective antibody levels for both

23F and 6B at 1.5 years

RA and SpA separately

RA patients

persistence of protective antibody levels

B p-value OR 95% CI

Lower Upper

Age /10 years (years) -0.06 0.238 0.97 0.93 1.02

Disease duration (years) 0.03 0.051 0.94 0.89 1.00

Ongoing MTX (yes/no) -1.54 0.038 0.22 0.05 0.92

Ongoing anti-TNF (yes/no) -1.25 0.070 0.29 0.07 1.11

HAQ (0-3) -0.29 0.543 0.75 0.29 1.91

Prevaccination antibody

levels for 23F (mg/L)* 1.43 0.001 4.19 2.51 6.98 * The same pattern was seen when correction for prevaccination antibody levels for serotype 6B was performed in the analysis

SpA patients

persistence of protective antibody levels

B p-value OR 95% CI

Lower Upper Age /10 years (years) -0.05 0.014 0.95 0.91 0.99

Ongoing MTX (yes/no) -1.02 0.073 0.36 0.12 1.10 Ongoing anti-TNF (yes/no) -0.28 0.618 0.76 0.25 2.26 Prevaccination antibody levels for 23F (mg/L)* 1.48 0.001 4.36 2.26 8.46

* The same pattern was seen when correction for prevaccination antibody levels for serotype 6B was performed in the analysis

Conclusion

• Postvaccination antibody levels were significantly lower 1.5 years after pneumococcal vaccination compared to levels 4-6 weeks after vaccination

• Persistence of protective immunity against the serotypes tested was shorter than reported in healthy individuals

– Musher et al, JID, 2010

• Concomitant MTX treatment was associated with more rapid decline of protective antibodies after pneumococcal vaccination in patients with RA

• Revaccination earlier than recommended for healthy persons may be needed in patients with arthritis

Acknowledgement

We thank the late nurse Lotta Larsson, Elna Haglund, Eva-Karin

Kristoffersson, Helén Axelsson, Käthe Nilsson, Peter Kapral, Maria Jacobsson, Ingrid Moberg, Ingrid Bondesson, Ingrid Hermansson, Eva Hommerberg, Ingrid Mattsson-Geborek

We also thank all patients for their participation in the study and all colleagues for their cooperation and support during the study The study was supported by grants from the Swedish Rheumatism

Association, the Swedish Research Council, the Medical Faculty of the University of Lund, Alfred Österlund´s Foundation, The Crafoord Foundation, Greta and Johan Kock´s foundation and The King Gustaf V Foundation, and Lund University Hospital

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Antibody levels for 8 serotypes during a 5-year follow-up study.

Musher D M et al. J Infect Dis. 2010;201:516-524

Anti-inflammatory treatment remained unchanged in total 302 (RA=163 and SpA=139

Percentage of patients with protective antibody levels (1 mg/L) for serotype 23F 4-6 weeks after vaccination and at 1.5 years follow up in patients with rheumatoid arthritis (RA) and sponylarthropsathy (SpA) in differrent treatment groups

Percentage of patients with protective antibody levels (1 mg/L) for serotype 6B 4-6 weeks after vaccination and at 1.5 years follow up in patients with rheumatoid arthritis (RA) and sponylarthropsathy (SpA) in different treatment groups

Immune response ratio 23F

10t h, 25t h, m edian , 75t h, 90t h perc ent ile 1 10 100 Log scale RA MTX anti-TNFRA SpA anti-TNF SpA MTX anti-TNF RA MTX anti-TNF SpA Controls

Immune response ratio 6B

10t h, 25t h, m edian , 75t h, 90t h perc ent ile 1 10 100 Log scale RA MTX anti-TNFRA SpA anti-TNF SpA MTX anti-TNF RA MTX anti-TNF SpA Controls

Percent positive immune response 6B and 23F

P erc ent ( %) 0 20 40 60 80 RA

MTX anti-TNFRA anti-TNFSpA SpA MTX anti-TNF RA MTX anti-TNF SpA Controls p=0.007 ns p<0.002 ns p=0.027

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Ln ant ibody lev els -6 -4 -2 0 2 4 6 8 at vaccination at 4-6 weeks after vaccination at 1.5 years follow up

RA on MTX RA on anti-TNF

monotherapy RA on anti-TNF+ MTX SpA on anti-TNFmonotherapy SpA on anti-TNF+ MTX SpA on NSAID/analgesics