Ref.

Study* design

Population

n

anti-TNF-α therapy (n)

Patients on methotrexate (%)

Vaccines

Effect in RA patients

Lower responsei

[16]

P, DB, R, PC, MC

RA
RA

99
109

a (99)
---

56.0
54.0

PPV
and TIV

PPV: Vaccine responsesa in adalimumab (37.4%) and placebo group (40.4%) and percentages of individuals with protective antibody titersb (adalimumab: 85.9%; placebo: 81.7%) similar
TIV: Percentages of responding RA patients on adalimumab (51.5%) lower than in the placebo group (63.3%)
RA patients without protective antibody titers at baseline: percentages of responding adalimumab-treated patients (73.3%) similar to the placebo group (73.9%), as well as percentages of individuals with protective antibody titers after vaccination (adalimumab: 98%; placebo: 94.5%)

No

 

Yes

No

No

[17]

C, SC

RA
AS
HC

43
18
17

i (20)
i (18)
---

81.3
66.7
---

TIV

RA patients vaccinated 3 weeks after administration of infliximab: increase of geometric mean titers (GMTs) was not significant for H1N1 and H3N2
Percentage of respondersc similar in all groups

Yes

 

No

[18]

P, C, SC

Anti-TNF- α (n=120): RA
AS
PsA
DMARDs alone (n=116):
RA
AS
PsA
HC

 

41
57
22

 

41
75
53
117

e (26)
a+i (94)

 

 

 

---
---
---
 ---

35.8

 

 

 

53.4

pIV

Similar seroconversion ratesd compared to 117 healthy controls
Negative effect of methotrexate on the vaccine-specific response

No

[19]

P, MC

RA
JIA
HIV
Cancer
KTX
Elderly

258
83
255
319
85
149

n. r.

n. r.

pIV

Proportions of seroprotection, seroconversiond and GMT ratios post-vaccination were 61.5%, 53.1% and 7.5 similar to elderly persons ≥60 years of age (63.1%, 55.7% and 5.7)

No

[20]

C, SC

RA
PsA
AS
SLE
HC

41
17
15
21
25

a/e/i (3/5/5)
(4/4/6)
(2/2/8)
---
---

61.0
41.2
6.7
14.3
---

pIV

Significant increase of GMTs in RA patients (5.7 to 64.3) (HC: 4.3 to 127)
Proportion of respondersc significantly lower in RA patients (56%) compared to HC (84%)
Seroprotection ratesd slightly lower in RA patients (71%) compared to HC (92%)

No

Yes

Yes

[21]

P, C, SC

RA
ORD
HC

343
1325
234

n. r.
n. r.
---

n. r.
n. r.
---

pIV

Factor increase of GMT in RA patients (7.2) lower than in HC (13.2)
Seroconversion rated in RA patients (53.4%) lower than in HC (76.9%)
Seroprotection rated in RA patients (60.1%) lower than in HC (82.9%)

Yes
Yes
Yes

[22]

P, C, SC

RA
HC

340
234

a/e/i (16/11/20)
---

63.2
---

pIV

Lower GMTs (71.9), factor increase in GMTs (9.6) and post-vaccination seroprotection ratesd (67.4%) in RA versus HC (122.9, 13.2 and 82.9%, respectively)

Yes

[25]

C, SC

RA
HC

149
18

n. c. (112)
---

58.4
---

TIV

Postvaccination GMT increased significantly compared to pre-vaccination titers in all treatment groups and controls

No

[26]

C, SC

RA
HC

82
30

i/e (22/5)
---

68.3
---

TIV

Similar GMTs in RA compared to HC for all influenza antigens
Percentage of responders to B antigen lower in RA (67%) than in HC (87%)

No
Yes

[27]

C, SC

RA
ORD

79
33

RA + ORD: a/e/i (21/14/29)

RA + ORD: 71.0

TIV

Lower postvaccination GMTs by anti-TNF-α treatment,
without lowering protection rates

Yes
No

[28]

C, SC

RA
HC

28
10

n. c.
---

n. r.
---

TIV

Similar response in seroconversion and seroprotection ratesd and in seroconversion factore

No

[30]

R, PC, MC

RA

70

i (56)

71.4

PPV

Although 80% to 85% of patients in the treatment groups respondedf to at least one serotype, only 20% to 25% responded to ≥6 different serotypes

Yes

[31]

C, SC

RA
HC

149
47

e/i (48/64)
---

58.4
---

PPV

Immunization responseg was similar between RA and HC against serotype 23F and 6B

No

[32]

SC

RA

31

e/i (12/4)

65.0

PPV

Significant increase of GMTs to all 7 serotypes tested
Lower proportions of RA patients on anti-TNF-α therapy with a >2-fold increase (e. g. 23F: 13% versus 53% not treated with anti-TNF-α)

No
Yes

[34]

MC

RA
SpA

253
252

n. c. (168)

RA + SpA: 68.8

PCV

Antibody response ratioh was higher in RA patients receiving anti-TNF-α alone (36.7%) compared to RA patients with methotrexate alone (21.2%) and anti-TNF-α and methotrexate (15.7%)

No

[35]

C, MC

RA†
RA
HC

253†
149
47

n. c.† (168)
n. c. (112)
---

68.8†
58.4
---

PCV† and PPV

Positive antibody response ratios and the positive antibody responseh were similar between the groups for the tested serotypes 23F and 6B

No

aA response to the vaccine was defined by a ≥ 2-fold titer increase from baseline at day 8 in ≥ 3 of 5 pneumococcal antigens and ≥ 4-fold increase from baseline in ≥ 2 of 3 influenza antigens [16]
bProtective antibody titers were defined by pneumococcal antibody concentrations ≥ 1.6 μg/ml to ≥ 3 of 5 antigens and by influenza antibody titers ≥ 1:40 to ≥ 2 of 3 antigens at 4 weeks after vaccination [16]
cA response to the vaccine was defined by a ≥ 4-fold rise in hemagglutination inhibition (HI) antibodies 4 to 6 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies <1:40 [17]
dSeroprotection was defined by influenza antibody titers ≥1:40 and seroconversion by pre-vaccination titer <1:10 and a post-vaccination HI titer ≥ 1:40 or a pre-vaccination titer ≥ 1:10 and a ≥ 4-fold increase postvaccination [18]
eThe seroconversion factor was calculated by the post-vaccination antibody titer divided by the pre-vaccination antibody titer and was considered as cut-off level of vaccine immunogenicity for adults 18-60 years when exceeding 2.5 (2.0 in people aged >60 years) [28]
fA response was defined if postvaccination antibody levels met the threshold value used by Quest Diagnostics (Van Nuys, CA) or if there was a ≥ 2-fold increase in pre- to postvaccination antibody levels in ≥ 6 of the 12 serotypes [30]
gThe immunization response was calculated as ratio of post- and prevaccination concentrations [31]
hA positive antibody response was defined as the antibody response ratio (ratio of post- to prevaccination antibody levels) of ≥ 2 [34,35]
iResponse of RA patients compared to the comparator in the study
†Identical with [34]
*Study design is given as described in the corresponding reference

Abbreviations

Ref: Reference; P: Prospective Study; DB: Double-Blind Study; C: Controlled Study; PC: Placebo-Controlled Study; R: Randomized Study; SC: Single-Center Study;
MC: Multi-Center STUDy; RA: Rheumatoid Arthritis; SpA: Spondylopathic Arthritis; AS: Ankylosing Arthritis; PsA: Psoriatic Arthritis; HC: Healthy Controls; KTX: Kidney Transplantation; JIA: Juvenile Idiopathic Arthritis; HIV: Human Immunodeficiency Virus; SLE: Systemic Lupus Erythematosus; ORD: Other Rheumatic Diseases; n. r.: not reported; n. c.: not classified for different anti-TNF-α agents; DMARDs: Disease-Modifying Anti-Rheumatic Drugs; a: adalimumab; e: etanercept; i: infliximab; PPV: 23-valent Pneumococcal Polysaccharide Vaccine; PCV: 7-valent Pneumococcal Conjugated Vaccine; TIV: Trivalent Influenza Vaccine; pIV: pandemic H1N1 influenza vaccine; GMT: Geometric Mean Titer
Table 1: Effect of anti-TNF-α therapy in rheumatoid arthritis patients on antibody responses to vaccinations.