Table 4

Efficacy, immunogenicity and safety of trivalent influenza vaccination in patients with AIIRD (October 2009–August 2018)

First author +ref.YearStudy designNo. casesEfficacyImmunogenicitySafetyInfluence of IS on eff./imm.LoE
Eff. Imm. Saf.
Subesinghe75 2018Meta-analysis7 studies in RASee column influence of ISMTX and anti-TNF not associated with reduced immunogenicity2a
Huang42 2017Meta-analysis13 studies in RA (also including pts <18 years)Reduced immunogenicity RA compared with HCs for H1N1 strain, not for H3N2 and B
Respective SP: 60%, 68%, 61%
Lower response with non-adjuvanted vaccine
Disease activity not influenced by vaccination
AE significantly more frequent in RA (RR 1.77; 95% CI 1.02 to 3.08)
GC: No influence
Anti-TNF, RTX: Lower SP rate for H1N1, but not for SC or other strains
Other biologics: Lower SP and SC for H1N1
Burmester201 2017Meta-analysisTotal in analysis:
171 RA-anti-TNF vacc.
382 RA-anti-TNF- non-vacc.
All using adalimumab
Influenza-related AE occurred in 5% of vaccinated pts versus 14% of non-vacc.2a
Hua77 2014Meta-analysis7 studies in RASee column influence of ISRTX: reduced immunogenicity
Anti-TNF: no influence
For MTX, results differed depending on method of analysis
Park79 2018RCT2 RA groups:
  • 156 MTX-cont.

  • 160 MTX hold for 2 weeks postvacc.

Better response for all strains in patients who hold MTX 2 weeks after vaccination (SP difference H1N1 11% (95% CI 2% to 19%), H3N2 16% (6% to 26%), B 14.7% (5% to 25%)No SAE
eight flares (5%) in MTX-cont. and 17 (11%) in MTX-hold group (p=0.07)
Park78 2017RCT4 RA groups on MTX:
  1. 54 cont.

  2. 44 hold 4 weeks pre,

  3. 49 hold 2 weeks pre/2 weeks post

  4. hold 4 weeks postvacc.

Adequate response
Better results in pts who stopped MTX 2 weeks before and after vaccination
Flares tended to be more common in groups 2 and 3 (not significant)
Kivitz202 2014RCT107 RA-CZP
109 RA-PCB
No differenceNo difference in AE:
62.3% in PCB versus 63.6% in CZP, mostly mild/moderate
Disease activity NR
Reduced on MTX1b-2b4
Chen34 2018Cohort (retrospective database)3748 RA-vacc
3748 RA non-vacc
Reduced risk of morbidity and mortality in vaccinated pts2b
Jain39 2017Cohort51 RA-MTX
51 RA-naïve
45 HCs
No differenceNo influence on disease activity
No difference in AE
See column immunogenicity2b4
Part A
2016Cohort102 RA-TFC
Similar proportions of satisfactory responseReduced in TFC/MTX2b
Part B
2016Cohort92 RA-TFC cont. 91 RA-TFC stopNo differenceNo2b
Alten83 2016Cohort184 RA ABT+MTXAdequate responseSee column immunogenicity2b
Luque Ramos203 2016Cohort (retrospective database)111482 RA
555410 HCs
Trend towards higher hospital admittance rates for pneumonia in areas with lower influenza and pneumococcal vaccine uptake5
Kogure74 2014Cohort57 RA:
9 biologics
34 MTX
10 GC
Seroprotection: H1N1 63%,
H3N2 81%, influenza B 26%
No change in disease activity, no AE.Reduced on biologics2b4
Both seasonal and pandemic
2014Cohort30 RA
13 HCs
No differenceMilder AE in patients.
No changes in disease activity
No effect of anti-TNF or ABT2b4
Kobashigawa36 2013Cohort (prospective)17735 RA in 4 seasons
(12.2%–38.7% vacc)
Vaccination associated with reduced self-reported risk of influenzaNo2b
Milanovic37 2013Cohort19 SLE–vacc.
11 SLE
15 RA-vacc.
22 RA
13 SjS-vacc.
19 SjS
Lower incidence of influenza and bact. Complications among vaccinated ptsSign. difference in GMT between vacc./unvacc.
SLE, but not in RA and
No changes in disease activityNo42b4
Tsuru81 2013Cohort38 TCZ
(28 RA/10 CD)
39 RA anti-TNF/DMARD
No differenceNo2b4
Mori73 2012Cohort62 RA-TCZ
18 RA-DC
Adequate immune response, but lower on MTXNo systemic AE
No flares
Reduced on MTX2b4
Kogure72 2012CohortRA treated with Japanese Kampo medicine:
16 RA-DC
No difference
Low response in general
No influence on disease activity
No influence of MTX44
Arad38 2011Cohort29 RA-RTX (16<5 mo, 13>5 mo)
17 RA-DC
16 HCs
Humoral immunity: reduced in RA-RTX
Similar percentage of influenza-specific IFN-γ producing CD4+ cells in RA groups
No change in disease activityHumoral immunity:
Reduced on RTX
Cellular immunity: No
Kobie40 2011Cohort61 RA-anti-TNF
33 RA-DC
97 HCs
Reduced in RA-anti-TNFReduced on anti-TNF2b
Rehnberg107 2010Cohort11 RA 6 mo post-RTX
8 RA 6 d pre-RTX
10 RA-DC
Lower frequency influenza-specific B cells in peripheral blood in post-RTX group 6 d after vacc.
Lower humoral response 21 d after vacc. in post-RTX group
Reduced on RTX4
Salemi71 2010Cohort22 RA-anti-TNF
10 HCs
Lower in RANo SAE
No difference in AE
No change in disease activity
ANA appearance/increase similar RA and HCs
Huang47 2016Meta-analysis15 studies in SLE (also including pts<18 years)Reduced immunogenicity SLE compared with HCs for H1N1 and B, but not for H3N2
Respective SP: 66%, 64%, 60%
Lower response with non-adjuvanted vaccine
Disease activity not influenced by vaccination
No difference in AE between SLE and HCs
GC, AZA or IS in general: reduced immunogenicity
HCsQ: No difference
Pugès45 2016Meta-analysis17 studies in SLEImmunogenicity depends on viral strains: reduced against A and preserved for BNo influence on disease activity2a2a
Liao46 2016Meta-analysis18 studies in SLEReduced in SLE for H1N1 and H3N2, but not for B
Respective SP: 68%, 76%, 66%
All side effects mild and transient
Similar rate of AE in SLE and HCs
2 severe flares
Chang35 2016Cohort (retrospective database)1765 SLE-vacc.
8360 SLE non-vacc.
Reduction of complications of influenza in vaccinated patients2b
Launay204 2013Cohort27 SLEPercentages of responders at day 30 are 55.5%, 18.5% and 55.5%, for H1N1, H3N2 and influenza B, respectivelyIncrease in rheumatoid factor levels, after vacc.
No flares.
Vista205 2012Cohort101 SLE
101 HCs
Similar proportion new onset anticardiolipin antibodies4
Crowe44 2011Cohort72 SLE
72 HCs
No difference.
More high responses in
African-American subjects.
19.4%/26.4% flare 6/12 weeks postvacc.
More low responders with flare at 6 weeks.
Reduced on steroids44
Wallin43 2009Cohort47 SLE:
  • 23 GC

  • 8 MTX

  • 9 AZA

27 HCs
No difference in seroprotectionOverall stable diseaseReduced on steroids2b4
Jaeger53 2017Cohort107 injections influenza vaccine in
AE in 7% of injections
Fever in 2%
Caso51 2016Cohort25 PsA-vacc.
25-PsA DC
Higher tender
joint count and
ESR after 1 month, more episodes mild symptoms in
PsA- vacc.
Jeffs48 2015Cohort24 AAV-vacc.
67 AAV-non vacc.
53 HCs
Adequate, but lower response in AAVNo SAE
Significant increase in local AE following vaccination only in HCs
No change in disease activity
Polachek50 2015Cohort63 PsA
4 Pso
30 HCs
No differenceIncreased CRP in patients 4–6
weeks postvacc.
Litinsky49 2012Cohort26 SSc
16 HCs
Increased in SSc for H1N1
No difference for H3N2 and influenza B
Overall stable diseaseIncreased on combination iloprost and calcium channel blockers for H1N1 and influenza B2b4
Both seasonal and pandemic
2012Cohort74 systemic vasculitis
32 SSc
29 SLE
23 SjS
28 other AIIRD
No difference19 flaresNo44
  • The table is structured as follows: First studies in RA, then SLE followed by other autoimmune inflammatory rheumatic diseases (AIIRD). Within this organisation, articles are clustered in study design (meta-analyses, RCT, cohort studies, case series) and presented in order of publication year.

  • AAV, ANCA-associated vasculitis; ABT, abatacept; ANA, antinuclear antibodies; AZA, azathioprine; bact., bacterial; CAPS, cryopyrin associated periodic syndrome; CD, Castleman’s disease; CD, cluster of differentiation; cont., continued; CRP, C reactive protein; CZP, certolizumab pegol; d, days; DC, disease control; DMARD, disease-modifying antirheumatic drug; eff., efficacy; ESR, erythrocyte sedimentation rate; GC, glucocorticoids; GMT, geometrical mean titre; HC, healthy controls; HCQ, hydroxychloroquine; IFN, interferon; imm, immunogenicity; IS, immunosuppressives; LoE, level of evidence; mo., months; MTX, methotrexate; No., number; NR, not reported; PCB, placebo; PsA, psoriatic arthritis; Pso, psoriasis; pts, patients; RA, rheumatoid arthritis; RCT, randomised controlled trial; ref., reference; RR, relative risk; RTX, rituximab; (S)AE, (serious) adverse event(s); saf., safety; SASP, salazosulfapyridine; SC, seroconversion; sign, significant; SjS, Sjögren’s syndrome; SLE, systemic lupus erythematosus; SP, seroprotection; SSc, systemic sclerosis; TAC, tacrolimus; TCZ, tocilizumab; TFC, tofacitinib; TNF, tumor necrosis factor; vacc., vaccinated; yrs, years.