Study

Author

Type

MTX Arms

Vaccine

Study size

Measurement of immune response

Mean MTX dose, mg/week ± SD

Vaccine Response at 3-6 weeks

Ref

1

Winthrop KL, et al. 2017

RCT

MTX vs MTX+TOF

Live VZV

112 Total: MTX 55, MTX+TOF 57

GMFR for IgG and T cell response

MTX 16.9±4.3, MTX+TOF 17.1±4.7

GMFR IgG GMT (80% CI): MTX + TOF 2.11 (1.87–2.37), MTX 1.74 (1.55–1.95), Ratio of MTX+TOF/MTX: 1.21 (1.03–1.42) GMFR T cell response (80% CI): MTX+TOF 1.50 (1.31–1.70), MTX 1.29 (1.14–1.46), ratio MTX +TOF/MTX 1.21 (1.03–1.42)

10

2

Park JK, et al. 2018

RCT

MTX-cont vs MTX-hold 2-week post vac

Influenza (H1N1, H3N2, B-Yamagata and B-Victoria)

316 Total: MTX-cont 156, MTX-hold 160

≥Fourfold increase of HIA titer against ≥2 of four vaccine strains

MTX-cont 13.3±3.4, MTX-hold 13.1±3.2

MTX-hold 75.5% vs MTX-cont 54.5% p<0.001 (difference 21.0%, 95% CI 10.6% to 31.7%)

11

3

Winthrop KL, et al. 2016

RCT and LTE

MTX vs MTX+TOF

Pneumococcal, Influenza (A/H1N1, A/H3N2, B)

200 Total: MTX (mono or with TOF) 112, No MTX (includes TOF mono) 88

≥Fourfold HIA titer of ≥ 2 of 3 influenza vaccine strains and ≥twofold titer increases of ≥ 6 of 12 pneumococcal serotypes

Inclusion range: ≥10 but ≤ 25

Pneumococcal, n/N (%): MTX 52/112 (46.4%) vs No MTX 61/88 (69.3%) Influenza, n/N (%): MTX 61/112 (54.4%) vs No MTX 58/88 (65.9%)

12

4

Ribeiro A, et al. 2011

CT

MTX vs No MTX

Influenza (H1N1)

340 Total: Yes MTX 215, No MTX 125

≥Fourfold increase of HIA titer, SRP (% with titer 1:40), SCR (% with ≥ fourfold increase in vac titer if prevac titer ≥ 1:10 or postvac titer≥ 1:40 if prevac titer <1:10.

Not reported

GMFR GMT (95% CI): MTX 5.5 (4.6-6.7), No MTX 11.4 (8.4-15.4), p<0.05 SC % (95% CI): MTX 46.3 (39.6-53.0), No MTX 65.3 (56.9-73.7), p<0.05 SP % (95% CI): MTX 53.2 (46.6-59.9), No MTX 71.8 (63.8-79.7), p<0.05

13

5

Kapetanovic MC, et al. 2014

CT

MTX vs No MTX receiving 1 vaccine dose compared to 2 vaccine doses

Influenza (H1N1)

291 Total: 123 received 1 dose (MTX 51, No MTX 72), 168 received 2 doses (MTX 103, No MTX 65)

18 to 60-years old (>60-years-old) if ≥1 of 3 criteria is fulfilled: SPR 70% (60%); SCR 40% (30%) or GMFR) >2.5 (3). SP (postvac titers ≥400), SC (prevac titers <10 and postvac HI titers ≥40 or a ≥4-fold increase in HI titers)

Not reported

1 dose SP. n/N (%): MTX 23/51 (45.1), No MTX 53/72 (73.6) 1 dose SC, n/N (%): MTX 21/53 (45.1), No MTX 40/72 (55.6) 2 dose SP: n/N (%): MTX 58/103 (56.3), No MTX 48/65 (73.8) 2 dose SC, n/N (%): MTX 47/103 (45.6), No MTX 44/65 (67.7)

14

6

Kapetanovic MC, et al. 2006

CT

TNF vs MTX+TNF vs MTX vs healthy control (healthy)

Pneumococcal

196 Total: RA 149 (MTX +TNF 50, MTX 37, TNF 62) and healthy 47

≥Twofold increase in antibody concentration

MTX 15, range 7.5-25. MTX +TNF 15, range 5-25

Immunization response 23F, ratio (range): TNF 2.8 (0.9–68), MTX+TNF 2.0 (0.7–36), MTX 1.4 (0.3–15), healthy 2.3 (0.2–91) , p<0.05 comparing TNF vs MTX+TNF, TNF vs MTX) Immunization response 6b, ratio (range): TNF 3.4 (0.8–280), MTX+TNF 1.8 (0.9–44), MTX 1.6 (0.8–20), healthy 2.2 (0.4–75) , p<0.05 comparing TNF vs MTX+TNF, TNF vs MTX, TNF vs healthy

15

7

Bingham III CO, et al. 2009

CT

MTX vs MTX+RTX

Tetanus toxoid, Pneumococcal, KLH, delayed type hypersensitivity with Candida albicans

103 Total enrolled: MTX 34, MTX+RTX 69. Completed: MTX 28, MTX+RTX 65

≥Fourfold rise in IgG levels and indurated response >5mm to C. albicans

MTX 16.4± .3, MTX+ RTX 17.2±4.2

Tetanus toxoid, n (%): MTX 11 (42.3%), MTX +RTX 25 (39.1%), −3.2 % difference (95% CI −25.7, 19.2) C. albicans, n (%): MTX 14 (70.0%), MTX+RTX 24 (77.4%), 7.4 % difference (95% CI−17.5, 32.3) Pneumococcal with at least 2 serotypes: MTX 82, MTX+RTX 43 GMT for KLH: MTX 1,585.5 titer units (95% CI 1,065.15-2,360.17), MTX+RTX 539.5 titer units (95% CI 461.54- 630.61).

16

8

Mori S, et al. 2013

CT

TCZ vs MTX+TCZ vs MTX vs RA Control (control)

Pneumococcal

190 Total: TCZ 50, MTX+TCZ 54, MTX 62, control 24

≥Twofold increase in GMC IgG concentration or a ≥Tenfold increase in the OIs

MTX+TCZ 8 (6 to 8) mg, MTX 8 (6 to 8) Note range indicates 25th and 75th percentile

GMFR IgG GMC Pneumococcal 6b, μg/ml, (95% CI): TCZ 2.8 (1.4-4.4), MTX+TCZ 1.6 (1.2-1.9), MTX 1.5 (1.1-3.0), control 1.8 (1.3-3.7), p<0.05 MTX+TCZ vs TCZ GMFR IgG GMC Pneumococcal 23F, μg/ml, (95%CI): TCZ 3.4 (1.5-6.8), MTX+TCZ 2.9 (1.0-6.9), MTX 2.6 (1.4-4.1), control 3.5 (1.7-5.6) GM-OI 6b (95%CI): TCZ 12 (3.5 to 62.4), MTX+TCZ 6.8 (1.7-35.5), MTX 4.5 (1-12.5), control 8.5 (2.2-52.0), p=0.001 for TCZ vs MTX GM-OI 23F (95% CI): TCZ 18.8 (2.7-75.1), MTX+TCZ 5.0 (1- 40), MTX 7.0 (2.7-15.8), control 11.0 (3.1-30.6), p=0.001 for TCZ vs MTX

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9

Mori S, et al. 2012

CT

TCZ vs MTX+TCZ vs MTX vs RA Control (control)

Influenza (A/H1N1, A/H3N2 and B/B1 strains)

194 Total: TCZ 62, MTX+TCZ 49, MTX 65, RA control 18

≥Fourfold increase in HIA titers in patients whose prevac titers were ≥10

MTX+TCZ 8 (6 to 8) mg/week, MTX 8 (6 to 8) mg/week. Note range indicates IQR

GMFR GMT A/H1N1 (95% CI): TCZ 12.0 (9.8–17.7), MTX+TCZ 14.5 (7.2–21.9), MTX 12.6 (5.8–19.5), control 11.2 (3.0–19.4) GMFR GMT A/H3N2 (95% CI): TCZ 12.0 (6.6–17.3), MTX+TCZ 9.9 (5.2–14.6), MTX 9.6 (5–14.2), control 5.3 (2.7–8.0) GMFR GMT B/B1 (95% CI): TCZ 5.0 (3.3–5.7), MTX+TCZ 5.4 (2.4–8.3), MTX 3.5 (2.5–4.4), control 5.8 (3.1–8.4)

18

10

Bingham CO 3rd, et al. 2015

RCT

MTX vs TCZ+MTX

Pneumococcal and Tetanus toxoid

91 Total: MTX 31, MTX+TCZ 60

≥Twofold or >1 mg/L increase from baseline in ≥6/12 pneumococcal antibody serotypes, ≥ Fourfold increase in tetanus toxoid antibody levels

Range for both MTX and MTX+TCZ 7.5–25 

Pneumococcal responders, n (%) (95% CI): MTX 17 (70.8%) (52.6 -89.0), MTX +TCZ 30 (60.0%) (46.4-73.6) Tetanus toxoid responders, n (%) (95% CI): MTX 9 (39.1) (19.2-59.1) MTX+TCZ 21 (42.0) (28.3-55.7)

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11

Calabrese LH, et al. 2020

post hoc analysis of RCT

TOF vs MTX+TOF vs MTX+ADM

Live VZV

1146 Total: 216 Vaccinated: TOF 69, MTX+TOF 75, MTX+ADM 72. 930 Non-Vaccinated: TOF 315, MTX+TOF 301, MTX+ADM 314

IR for Herpes Zoster

MTX+ TOF 16.0±3.8, MTX+ADM 17.1±3.6

IR for HZ for vaccinated (95% CI): TOF 1.5 (0.0–8.3), MTX+TOF 3.0 0.4–10.8), MTX+ADM 0 (0.0–5.8) IR for HZ for Non-vaccinated (95% CI): TOF 1.0 (0.2–3.0), MTX+TOF 2.2 (0.8–4.7), MTX+ADM 2.1 (0.8–4.5)

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12

Park JK, et al. 2016

RCT

MTX-cont, MTX-hold 4W pre-vac, MTX-hold 2W pre and 2 W post-vac, MTX-hold 4W post-vac

Influenza (H1N1, H3N2 and B-Yamagata)

199 Total: MTX-cont 54, MTX 4 weeks pre-44, MTX 2-week pre and post 49, MTX 4-week post 52

≥Fourfold HIA titer increase

MTX-cont 12.7±3.7, MTX 4W pre-13.3±3.4, MTX 2W pre and post 13.6±2.9, MTX 4W post 13.2±3.3

Response ≥2 antigens (%): MTX-cont 53.7, MTX 4 weeks pre-52.3, MTX 2 weeks pre and post 71.4, MTX 4 weeks post 65.4 Response ≥3 antigens (%): MTX-cont 31.5, MTX 4 weeks pre-22.7, MTX 2 weeks pre and post 51.0, MTX 4 weeks post 46.2, p=0.044 for MTX-cont vs MTX 2 weeks pre and post

21

13

Kapetanovic MC, et al. 2007

CT

TNF vs MTX+TNF vs MTX vs healthy control (healthy)

Influenza (H1N1, H3N2 and B1 or B2 Strain)

149 Total: TNF 62, MTX+TNF 50, MTX 37, healthy 18

≥Fourfold antibody titer increase, titer level ≥ 40

Not reported

Responders, n/N (%) H1N1: MTX 33/37 (89.2), MTX+TNF 26/50 (52.0), TNF 36/52 (58.1), healthy 14/18 (77.8) Responders, n/N (%) H3N2: MTX 28/37 (75.7), MTX+TNF 28/50 (56.0), TNF 46/62 (74.2), healthy 13/18 (72.2) Responders, n/N (%) B1: MTX 35/37 (94.6), MTX+TNF 42/50 (84.0), TNF 54/62 (87.1), healthy 12/18 (66.7)

22

14

Park JK, et al. 2019

CT

MTX-cont vs MTX-hold 2-week post vaccination

Influenza (H1N1, H3N2, B-Yamagata and Victoria)

316 Total: MTX-cont 156, MTX-hold 160

≥Fourfold increase in HIA titer

MTX-cont 13.3±3.4, MTX-hold 13.1±3.2

Response ≥2 antigen, n/N (%): MTX-cont 85/156 (54.5%), MTX-hold 121/160 (75.6%) Response ≥3 antigen, n/N (%): MTX-cont 57/156 (36.5%), MTX-hold 99/160 (61.9%)

23

15

Visvanathan S, et al. 2007

CT

INX+MTX vs MTX

Pneumococcal

70 Total: INX+MTX 56 and MTX 14

Postvac antibody levels met the threshold value used by Quest Diagnostics or ≥twofold increase in pre- to postvac antibody levels in ≥ 6 of the 12 serotypes

Dose ≥ 20: MTX 13 patients, MTX+INX 35 patients. Dose <20: MTX 1 patient, MTX+INX 21 patients

Responders receiving MTX ≥ 20 mg/week, n/N (%): MTX 3/13 (23.1%), MTX+INX 8/35 (22.9%) Responders receiving MTX < 20 mg/week, n/N (%): MTX N/A, MTX+INX 5/21 (23.8%)

24

16

Mease PJ, et al. 2004

CT

MTX vs No MTX, in patients ±ETC

Pneumococcal

184 Total: MTX 83, No MTX 101

≥Twofold increase in antibody titer

Not reported

Responders, n/N (%): MTX 19/83 (22.9%), No MTX 64/101 (63.4%), p< 0.0001

25

17

Kaine JL, et al. 2007

RCT

MTX vs No MTX

Pneumococcal and Influenza (H1N1, H3N2, and B Hong Kong)

208 Total: Placebo 50, MTX 59, MTX+ADM 55, ADM 44

≥Twofold increase in ≥ 3 of the 5 pneumococcal titers and ≥ Fourfold increase in ≥ 2 of the 3 influenza titers

Dose >0-10: MTX 16, MTX+ADM 17. Dose >10-15: MTX 21, MTX+ADM 19. Dose of >15: MTX 22, MTX+ADM 19

Pneumococcal responders, n/N (%): MTX 17/59 (28.8%), MTX+ADM 10/55 (18.2%), ADM 27/44 (61.4%), Placebo 27/50 (54.0), p < 0.001 for MTX use Influenza responders, n/N (%): MTX 33/59 (55.9%), MTX+ADM 29/55 (52.7%), ADM 22/44 (50.0%), Placebo 36/50 (72.0%)

26

18

Kapetanovic MC, et al. 2013

CT

MTX+RTX vs RTX

Pneumococcal

88 Total: RTX 29, MTX+RTX 26. Note other arms excluded with mixed MTX users and non-users

≥ Twofold increase in GMT

Mean dose: MTX+RTX 17.2

Post vac GMT mg/L (95% CI) 6b: RTX 0.4 (0.2-0.8), MTX+RTX 0.4 (0.2, 0.8). p not significant between RTX vs MTX+RTX Post vac GMT mg/L (95% CI) 23F: RTX 0.3 (0.2, 0.6), MTX+RTX 0.4 (0.2, 0.8) p not significant between RTX vs MTX+RTX

27

19

Kapetanovic MC, et al. 2011

CT

MTX vs MTX+TNF vs TNF vs NSAID control

Pneumococcal

505 Total: 253 RA: MTX 85, MTX+TNF 89, TNF 79. 252 SpA: MTX+TNF 83, TNF 83, NSAID control 85

Antibody response ratio (ARR) ≥ 2 (ratio of post to pre vaccine antibody levels)

RA (MTX 16.4, MTX+TNF 15.7). SpA (MTX+TNF 15.8)

ARR≥2, n (%): RA patients: MTX 18 (21.2), MTX+TNF 14 (15.7), TNF 29 (36.7). For SpA patients: MTX+TNF 22.5 (26.5), TNF 42 (50.6), control 41 (47.7). OR for all users of MTX 0.41 (95% CI 0.24-0.68)

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20

Ribeiro A, et al. 2013

CT

MTX vs healthy control (healthy)

Influenza (H1N1)

88 Total: MTX 33, healthy 55. ABT arm excluded due to mixed MTX users and non-users

FI in GMT, SP (% with titers ≥1:40), SCR (% with ≥fourfold increase in vac titers if the prevac titers were ≥1:10 or titers ≥1:40 if the prevac titers were <1:10)

MTX 25, range 15-25

FI-GMT n (95% CI): MTX 8.7 (5.2-17.4), healthy 11.5 (8.0-16.7) SP. n (%): MTX 19 (58), healthy 38 (69) SC. n (%): MTX 19 (58), healthy 36 (66)

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21

O'Dell JR, et al. 1996

CT

MTX vs RA control

Pneumococcal

40 Total: MTX 20, No MTX 20

Antibody levels ≤ 300µg/ml prevac and ≥ 300µg/ml post vac

MTX 13

Responders (%): MTX 55, No MTX 77, p=0.03

30

22

Migata K, et al. 2015

RCT

MTX vs MTX+GOM vs RA control

Pneumococcal

114 Total: RA control 35, MTX 55, GOM+MTX 24

≥Twofold increase in IgG concentrations, >tenfold increase in OI

MTX 7.8±2.37, MTX+GOM 8.33±2.55

FI 23F IgG: MTX 2.00 (1.27-5.48), MTX+GOM 1.41 (1.18-4.29), control 3.36 (1.85-9.42) FI 6b IgG: MTX 1.75 (1.15-3.11), MTX+GOM 1.23 (1.09-1.53), control 2.38 (1.41-5.62) OPA Titer 23F: MTX 3.75 (1.47-38.2), MTX+GOM 10.00 (1.33-38.49), control 6.86 (2.50-27.14) OPA Titer 6b: MTX 2.57 (1.22-22.40), MTX+GOM 6.58 (2.69-48.68), control 10.22 (1.92-79.48)

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23

Kivitz AJ, et al. 2014

RCT

MTX vs MTX+CZP vs CZP vs placebo

Pneumococcal, Influenza (H1N1, H3N2 B/Brisbane)

Receiving pneumococcal vac: MTX 60, MTX+CZP 63, CZP 25, placebo 28, Receiving influenza vac: MTX 57, MTX+CZP 59, CZP 27, Placebo 26

≥Twofold titers increase in ≥ 3 of 6 pneumococcal antigens and ≥Fourfold titer increase in ≥ 2 of 3 influenza antigens

MTX 17.2±5.0, MTX+CZP 15.9±4.6

Pneumococcal response, n/N (%) (95% CI): MTX 30/60 (50) (37.3-62.7), MTX+CZP 28/63 (44.4) (32.2-56.7), Placebo 25/28 (89.3) (77.9-100.0), CZP 20/25 (80) (64.3-95.7) Influenza response, n/N (%) (95% CI): MTX 29/57 (50.9) (37.9-63.9), MTX+CZP 27/59 (45.8) (33.1–58.5), Placebo 22/26 (84.6) (70.7–98.5), CZP 19/27 (70.4) (53.1–87.6)

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24

Kobie JJ, et al. 2011

CT

MTX vs MTX+TNF vs RA control vs healthy control

Influenza (H1N1, H3N2, and B strains)

261 Total: MTX 70, RA control 33, healthy control 97. TNF arm excluded due to mixed MTX and non- MTX users

HIA GMT

MTX 16.5±4.0

HAI responders cumulatively over 3 years at 1 month post vac, n/N (%): H1N1: MTX 61/68 (89.7), RA control 31/36 (86.1), healthy control 90/99 (90.9%) H3N2: MTX 55/79 (69.6), RA control 32/36 (88.9), healthy control 97/99 (98.0) B strain: MTX 59/68 (86.7), RA control 35/36 (97.2), healthy control 93/99 (93.9)

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25

Kapetanovic MC, et al. 2013

CT

RA patients: MTX, MTX+TNF, TNF. SpA patients: MTX+TNF, TNF, NSAID control

Pneumococcal

302 Total: 163 RA patients: MTX 85, MTX+TNF 89, TNF 79. 139 SpA patients: MTX+TNF 83, TNF 83, NSAID control 86

Post vac GMT with antibody levels ≥1 mg/L

Not reported

Responders for both 23F and 6b: RA: MTX 67, MTX+TNF 52, TNF 58. SpA: MTX+TNF 65, TNF 78, NSAID control 84 Responders for both 23F and 6b at 1.5-year follow-up: RA: MTX 40, MTX+TNF 20, TNF 32, SpA: MTX+TNF 49, TNF 60, NSAID control 70. Relative ratio at 1.5 year to 4-6week follow-up: RA: MTX 0.61, MTX+TNF 0.38, TNF 0.55. SpA MTX+TNF 0.75, TNF 0.77, NSAID control 0.84

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26

Migata K, et al. 2015

RCT

MTX vs TAC vs MTX+TAC

Pneumococcal

133 Total: of which 84 in MTX analysis: MTX 55, MTX+TAC 14, TAC 29

≥Twofold increase in IgG concentrations or a> 10-fold increase in OI

MTX 7.80± 2.37, MTX+ TAC 8.29±3.22

FI IgG GMCs for 23F, n (95% CI): MTX 2.00 (1.27-5.48), TAC 7.63 (3.70-18.85), MTX+TAC 1.85 (1.14-3.82), p= 0.005 for MTX vs TAC, p < 0.0001 for MTX+TAC vs TAC GM-OI for 23F, n (95% CI): MTX 3.75 (1.47-38.32), MTX+TAC 64.38 (11.59 -231.22), TAC 3.51 (1.00 to 8.00), p=0.048 for MTX vs MTX+TAC, p < 0.0001 for MTX+TAC vs TAC

35

27

Askling HH, et al. 2014

CT

MTX vs MTX+TNF vs TNF

Hepatitis A

53 Total: MTX 17, MTX+TNF 21, TNF 15

anti-HAV antibodies≥20mIU/mL

15, range of 7.5-22.5

Anti-HAV ≥20 mIU/mL at month 1, %: MTX 6, MTX+TNF 5, TNF 20 Using the lower level of protection (anti-HAV 10 mIU/L) at 1 month: MTX 6, MTX+TNF 15, TNF 73

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28

Migata K, et al. 2015

RCT

MTX vs RA control

Pneumococcal

111 Total: 90 in MTX analysis: MTX 55, RA control 35. ABT arm excluded due to mix of MTX users and non-users

≥Twofold increase in IgG concentrations or a> 10-fold increase in OI

MTX 7.8±2.4

FI IgG GMCs for 23F, n (95% CI): MTX 2.00 (1.27-5.48), control 3.36 (1.85- 9.42) FI IgG GMCs for 6b, n (95% CI): MTX 1.75 (1.15-3.11), control 2.38 (1.41-5.62) GM-OI 23F, n (95% CI): MTX 3.75 (1.47-38.32), control 6.86 (2.50-27.14) GM-OI 6b, n (95% CI): MTX 2.57 (1.22-22.40), control 10.22 (1.92-79.48)

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29

Bingham CO 3rd, et al. 2015

RCT

MTX vs MTX+TAB 120mg/Q4W vs MTX + TAB 90mg/Q2W

Pneumococcal, Tetanus Toxoid

69 Total: MTX 17, MTX+TAB 120/Q4W 21, MTX+TAB 90mg/Q2W 30

≥Twofold increase in IgG pneumococcal, ≥fourfold increase in IgG for tetanus toxoid

Not reported

Tetanus responders, n (%): MTX 10 (58.8), MTX+TAB 120/Q4W 17 (81.0), MTX+ TAB 90/Q2W 13 (43.3) Pneumococcal responders, n (%): MTX 13 (76.5), MTX+TAB 120/Q4W 15 (71.4), MTX+TAB 90/Q2W 23 (74.2)

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