Efficacy, immunogenicity and safety of trivalent influenza vaccination in patients with AIIRD (October 2009–August 2018)
| First author +ref. | Year | Study design | No. cases | Efficacy | Immunogenicity | Safety | Influence of IS on eff./imm. | LoE | ||
| Eff. | Imm. | Saf. | ||||||||
| Subesinghe75 | 2018 | Meta-analysis | 7 studies in RA | – | See column influence of IS | – | MTX and anti-TNF not associated with reduced immunogenicity | – | 2a | – |
| Huang42 | 2017 | Meta-analysis | 13 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 | – | 2a | 2a |
| Burmester201 | 2017 | Meta-analysis | Total 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 | 2014 | Meta-analysis | 7 studies in RA | – | See column influence of IS | – | RTX: reduced immunogenicity Anti-TNF: no influence For MTX, results differed depending on method of analysis | – | 2a | – |
| Park79 | 2018 | RCT | 2 RA groups:
| – | 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) | – | – | 1b-2b | 2b |
| Park78 | 2017 | RCT | 4 RA groups on MTX:
| – | Adequate response Better results in pts who stopped MTX 2 weeks before and after vaccination | No SAE Flares tended to be more common in groups 2 and 3 (not significant) | – | – | 1b-2b | 2b |
| Kivitz202 | 2014 | RCT | 107 RA-CZP 109 RA-PCB | – | No difference | No difference in AE: 62.3% in PCB versus 63.6% in CZP, mostly mild/moderate Disease activity NR | Reduced on MTX | – | 1b-2b | 4 |
| Chen34 | 2018 | Cohort (retrospective database) | 3748 RA-vacc 3748 RA non-vacc | Reduced risk of morbidity and mortality in vaccinated pts | – | – | – | 2b | – | – |
| Jain39 | 2017 | Cohort | 51 RA-MTX 51 RA-naïve 45 HCs | – | No difference | No influence on disease activity No difference in AE | See column immunogenicity | – | 2b | 4 |
| Winthrop84
Part A | 2016 | Cohort | 102 RA-TFC 98 RA-PCB | – | Similar proportions of satisfactory response | – | Reduced in TFC/MTX | – | 2b | – |
| Winthrop84
Part B | 2016 | Cohort | 92 RA-TFC cont. 91 RA-TFC stop | No difference | No | – | 2b | – | ||
| Alten83 | 2016 | Cohort | 184 RA ABT+MTX | – | Adequate response | – | See column immunogenicity | – | 2b | – |
| Luque Ramos203 | 2016 | Cohort (retrospective database) | 111482 RA 555410 HCs | Trend towards higher hospital admittance rates for pneumonia in areas with lower influenza and pneumococcal vaccine uptake | – | – | – | 5 | – | – |
| Kogure74 | 2014 | Cohort | 57 RA: 9 biologics 34 MTX 8 TAC 10 GC 14 SASP | – | Seroprotection: H1N1 63%, H3N2 81%, influenza B 26% | No change in disease activity, no AE. | Reduced on biologics | – | 2b | 4 |
| Milanetti41
Both seasonal and pandemic | 2014 | Cohort | 30 RA 13 HCs | – | No difference | Milder AE in patients. No changes in disease activity | No effect of anti-TNF or ABT | – | 2b | 4 |
| Kobashigawa36 | 2013 | Cohort (prospective) | 17735 RA in 4 seasons (12.2%–38.7% vacc) | Vaccination associated with reduced self-reported risk of influenza | – | – | No | 2b | – | – |
| Milanovic37 | 2013 | Cohort | 19 SLE–vacc. 11 SLE 15 RA-vacc. 22 RA 13 SjS-vacc. 19 SjS | Lower incidence of influenza and bact. Complications among vaccinated pts | Sign. difference in GMT between vacc./unvacc. SLE, but not in RA and SjS. | No changes in disease activity | No | 4 | 2b | 4 |
| Tsuru81 | 2013 | Cohort | 38 TCZ (28 RA/10 CD) 39 RA anti-TNF/DMARD | – | No difference | – | No | – | 2b | 4 |
| Mori73 | 2012 | Cohort | 62 RA-TCZ 65 RA-MTX 49 RA-TCZ +MTX 18 RA-DC | Adequate immune response, but lower on MTX | No systemic AE No flares | Reduced on MTX | – | 2b | 4 | |
| Kogure72 | 2012 | Cohort | RA treated with Japanese Kampo medicine: 24 RA+MTX 16 RA-DC | – | No difference Low response in general | No AE No influence on disease activity | No influence of MTX | – | 4 | 4 |
| Arad38 | 2011 | Cohort | 29 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 activity | Humoral immunity: Reduced on RTX Cellular immunity: No | – | 2b | 4 |
| Kobie40 | 2011 | Cohort | 61 RA-anti-TNF 70 RA-MTX 33 RA-DC 97 HCs | – | Reduced in RA-anti-TNF | – | Reduced on anti-TNF | – | 2b | – |
| Rehnberg107 | 2010 | Cohort | 11 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 RTX | – | 4 | – |
| Salemi71 | 2010 | Cohort | 22 RA-anti-TNF 10 HCs | – | Lower in RA | No SAE No difference in AE No change in disease activity ANA appearance/increase similar RA and HCs | – | – | 2b | 4 |
| Huang47 | 2016 | Meta-analysis | 15 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 | – | 2a | 2a |
| Pugès45 | 2016 | Meta-analysis | 17 studies in SLE | – | Immunogenicity depends on viral strains: reduced against A and preserved for B | No influence on disease activity | – | – | 2a | 2a |
| Liao46 | 2016 | Meta-analysis | 18 studies in SLE | – | Reduced 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 | – | – | 2a | 2a |
| Chang35 | 2016 | Cohort (retrospective database) | 1765 SLE-vacc. 8360 SLE non-vacc. | Reduction of complications of influenza in vaccinated patients | – | – | – | 2b | – | – |
| Launay204 | 2013 | Cohort | 27 SLE | Percentages of responders at day 30 are 55.5%, 18.5% and 55.5%, for H1N1, H3N2 and influenza B, respectively | Increase in rheumatoid factor levels, after vacc. No flares. | 4 | 4 | |||
| Vista205 | 2012 | Cohort | 101 SLE 101 HCs | – | – | Similar proportion new onset anticardiolipin antibodies | – | – | – | 4 |
| Crowe44 | 2011 | Cohort | 72 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 steroids | – | 4 | 4 |
| Wallin43 | 2009 | Cohort | 47 SLE:
27 HCs | – | No difference in seroprotection | Overall stable disease | Reduced on steroids | – | 2b | 4 |
| Jaeger53 | 2017 | Cohort | 107 injections influenza vaccine in 55 CAPS | – | – | AE in 7% of injections Fever in 2% No SAE | – | – | – | 4 |
| Caso51 | 2016 | Cohort | 25 PsA-vacc. 25-PsA DC | – | – | Higher tender joint count and ESR after 1 month, more episodes mild symptoms in PsA- vacc. | – | – | – | 4 |
| Jeffs48 | 2015 | Cohort | 24 AAV-vacc. 67 AAV-non vacc. 53 HCs | – | Adequate, but lower response in AAV | No SAE Significant increase in local AE following vaccination only in HCs No change in disease activity | – | – | 2b | 2b |
| Polachek50 | 2015 | Cohort | 63 PsA 4 Pso 30 HCs | – | No difference | Increased CRP in patients 4–6 weeks postvacc. | No | – | 2b | 4 |
| Litinsky49 | 2012 | Cohort | 26 SSc 16 HCs | – | Increased in SSc for H1N1 No difference for H3N2 and influenza B | Overall stable disease | Increased on combination iloprost and calcium channel blockers for H1N1 and influenza B | – | 2b | 4 |
| Kostianovsky52
Both seasonal and pandemic | 2012 | Cohort | 74 systemic vasculitis 32 SSc 29 SLE 23 SjS 28 other AIIRD | – | No difference | 19 flares | No | – | 4 | 4 |
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.