Table 1

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.