. 2021 Dec 22;181(4):1329–1362. doi: 10.1007/s00431-021-04283-w

Table 2.

Summary of findings of studies investigating the influence of immunosuppressive treatment on humoral vaccination responses in children and children with JARD

Author Country Publication year	Number of participants (% female), mean age (unless otherwise specified) Treatment Number of controls (% female), mean age (unless otherwise specified) Treatment (if any)	Study type (Level of evidence)	Vaccine (producer) Dosage Number of doses (interval)	Timing of blood sampling after last vaccination	Immunogenicity	Local reactions Systemic reactions Severe adverse events Worsening in disease activity	Additional findings
Enthesitis-related arthritis (ERA)
Measles, rubella
Maritsi et al. [43] Greece 2019	41 ERA (25%), 11.7 y (SD 4.3) 41 adalimumab initiated after vaccination, 25 MTX, 6 SSZ¹ 149 healthy, 11.8 y (SD 3.7)	Single-centre, prospective cohort study (2B)	Measles (NA) NA 2 (age 2 y and 5 y) Rubella (NA) NA 2 (age 2 y and 5 y)	12 m²	• Lower GMT for measles in ERA (190.0 (95%CI 138.0–264.0) vs 256.0 IU/mL (95%CI 159.0–294.0), p = 0.04) • Lower GMT for rubella in ERA (29.9 (95%CI 23.2–38.5) vs 41.6 IU/mL (95%CI 35.0–46.0), p < 0.01) • No difference in SPR for measles and rubella between ERA and controls	NA NA NA NA	No difference in GMT and SPR for measles and rubella for children who were only on adalimumab or on additional MTX or SSZ
36 m²	• Lower GMT for measles in ERA (167.0 (95%CI 124.0–256.0) vs 251.0 IU/mL (95%CI 107.0–264.0), p = 0.02) • Lower GMT for rubella in ERA (26.2 (95%CI 20.2–33.9) vs 41.0 IU/mL (95%CI 32.0–46.0), p < 0.01) • No difference in SPR for measles and rubella between ERA and controls	No difference in GMT and SPR for measles and rubella for children who were only on adalimumab or on additional MTX or SSZ
Juvenile dermatomyositis (JDM)
Human papillomavirus
Grein et al. [42] Brazil 2020	42 JDM (100%), median 16.0 y (IQR 13.0–19.0) 20 steroids, 17 hydroxychloroquine, 15 MTX, 11 none, 8 azathioprine, 7 cyclosporine, 2 IVIG, 1 mycophenolate mofetil¹ 35 healthy (100%), median 14.0 y (IQR 6.5–21.5)	Multicentre, prospective cohort study (2B)	Gardasil^®(NA) NA 3 (0; 1 m or 2 m; 6 m)	1 m	• No difference in SPR for HPV16 and HPV18 between JDM and controls	JDM: pain 57 (47%), induration 14 (12%), oedema 10 (8%), redness 7 (6%), bruise 1 (1%) Controls: pain 65 (59%), oedema 21 (19%), induration 18 (16%), redness 9 (8%), bruise 6 (5%)³ JDM: headache 25 (21%), fatigue 14 (12%), nausea 12 (10%), itchiness 11 (9%), muscular pain 4 (3%), new cutaneous abnormalities 4 (3%), articular pain 2 (2%), fever 2 (2%), vomiting 2 (2%) Controls: headache 27 (24%), fatigue 19 (17%), nausea 7 (6%), itchiness 2 (2%), muscular pain 2 (2%), fever 1 (1%)³ None JDM: 1 (2%)	No difference in SPR for HPV18 for different treatments 2 JDM (1 on MTX, 1 on hydroxychloroquine + steroids) did not reach seroprotection for HPV16 and HPV18 1 JDM (on azathioprine + hydroxychloroquine + steroids) did not reach seroprotection for HPV18
6 m	• SPR for HPV16 and HPV18 94% in JDM, values in controls NA	No difference in SPR for HPV16 and HPV18 for different treatments 1 JDM (on azathioprine + hydroxychloroquine + steroids) did not reach seroprotection for HPV 18
Influenza
Guissa et al. [23] Brazil 2012	30 JDM (63%), median 15.5 y (range 9.0–21.0, 7 children ≤ 18 y) 15 steroids, 14 MTX, 6 cyclosporine, 2 azathioprine, 7 chloroquine¹ 81 healthy (41%), median 15.0 y (range 9.0–21.0)	Single-centre, prospective cohort study (2B)	NYMCx-179A (Butantan Institute/Sanofi Pasteur) • A/California/7/2009(H1N1)pdm09 15 μg 1	21 d	• Lower SCR in JDM (87 (95%CI 75–99) vs 98% (95%CI 94–100), p = 0.04) • No difference in GMT and SPR between JDM and controls	JDM: pain 9 (30%) Controls: pain 19 (23%), swelling 2 (2%), redness 2 (2%), itching 1 (1%) JDM: headache 5 (17%), rhinorrhoea 4 (13%), arthralgia 1 (3%), fever 1 (3%), myalgia 1 (3%) Controls: headache 18 (22%), myalgia 6 (7%), cough 5 (6%), sore throat 5 (6%), fever 3 (4%), rhinorrhoea 3 (4%), nasal congestion 3 (4%), arthralgia 2 (2%), diarrhoea 2 (2%) None None	4 JDM did not reach seroprotection
Juvenile idiopathic arthritis (JIA)
Hepatitis A
Maritsi et al. [13] Greece 2017	83 JIA (66%), 6.3 y (SD 2.3) 83 MTX 76 healthy (45%), 5.3 y (SD 2.7)	Single-centre, prospective cohort study (2B)	Havrix^®(GlaxoSmithKline) 720 IU/mL 2 (0; > 6 m)	1 m	• Lower GMT in JIA (94.0 vs 162.5 mIU/mL, p < 0.01) • No difference in SCR and SPR between JIA and controls	JIA: 5 (6%) Controls: 4 (5%) JIA: fever 3 (4%), malaise 3 (4%) Controls: fever 2 (3%), malaise 2 (3%) None JIA: 15 (18%) (in 2 after the 1st dose and in 13 after the 2nd dose after a mean of 8 months)	No difference in GMT, SCR and SPR between different JIA subtypes (ERA, oligoarticular JIA with, polyarticular JIA, psoriatic JIA) No difference in GMT, SCR and SPR in JIA with or without presence of uveitis or ANA positivity
12 m	• Lower GMT in JIA (98.2 vs 200.3 mIU/mL, p < 0.01) • No difference in SCR and SPR between JIA and controls
Erguven et al. [35] Turkey 2011	47 JIA (51%), 10.7 y (SD 3.9) 19 SSZ, 18 MTX, 11 MTX + steroids, 4 etanercept, 1 steroids¹ 67 healthy (46%), 9.4 y (SD 3.8)	Single-centre, prospective cohort study (2B)	Hepatitis A (NA) NA 2 (0; 6 m)	2 m	• Lower SPR in JIA (92 vs 100%, p < 0.05)	None None None None
Hepatitis B
Kasapçopur et al. [16] Turkey 2004	39 JIA (46%), 10.0 y (SD 3.3, range 4.0–16.0) 19 MTX, 17 steroids, 3 MTX + steroids 41 healthy (51%), 8.8 y (SD 2.6, range 5.0–14.0)	Single-centre, prospective cohort study (2B)	Engerix-B^®(GlaxoSmithKline) 10 μg (weight < 20 kg), 20 μg (weight > 20 kg) 3 (0; 1 m; 3 m or 6 m)	1 m	• Lower GMT in JIA (137.4 vs 258.9 mIU/mL, p = NA) • Lower SPR in JIA (97 vs 100%, p = NA)	None None None NA	No difference in GMT for different treatments No difference in GMT for different vaccine schedules (3rd dose at 3 or 6 m)
Human papillomavirus
Heijstek et al. [44] Netherlands 2014	68 JIA (100%), 14.1 y (SD 1.6) 24 MTX, 9 anti-TNF-alpha, 5 leflunomide, 1 anti-IL-1, 1 mycophenolate mofetil¹ 55 healthy (100%), 14.3 y (SD 1.2)	Single-centre, prospective cohort study (2B)	Cervarix^®(GlaxoSmithKline) NA 3 (0; 1 m; 6 m)	1 m	• No difference in GMT between JIA and controls	JIA: pain 52 (96%), induration 26 (48%), swelling 25 (46%) redness 20 (37%), bruising 14 (26%) Controls: pain 44 (100%), redness 43 (98%), bruising 39 (89%), induration 21 (48%), swelling 18 (41%) JIA: fatigue 30 (56%), myalgia 29 (54%), headache 22 (41%), arthralgia 11 (20%), rash 11 (20%), fever 6 (11%), syncope 1 (2%) Controls: fatigue 22 (50%), headache 22 (50%), myalgia 19 (43%), arthralgia 6 (14%), rash 6 (14%), fever 3 (7%) JIA: endoscopies 3 (4%), pre-planned surgeries 2 (3%), allergic reaction to anti-TNF-alpha 1 (1%), analyse of gait abnormalities 1 (1%), appendicitis 1 (1%), correction of cerebral arteriovenous malformation 1 (1%), epileptic insult (cerebral arteriovenous malformation) 1 (1%), perforated eardrum 1 (1%), pre-planned laser therapy uveitis 1 (1%), severe pharyngitis 1 (1%) transient lower back pain 1 (1%), Controls: pre-planned surgery 1 (2%) None	1 JIA (on MTX) did not reach seroprotection at 6 m No difference in GMT between JIA on MTX and JIA on other treatments
6 m	• No difference in GMT between JIA and controls • No difference in avidity of HPV16/18-specific IgGs between JIA and controls
Diphtheria, tetanus
Brunner et al. [41] USA 2020	29 JIA (55%), 4.2 y (SD 0.9) 29 abatacept, 22 MTX, 3 steroids¹	Multicentre, cross-sectional study (2C)	Diphtheria and tetanus (NA) NA NA	NA	• SPR for diphtheria in JIA 90% • SPR for tetanus in JIA 100%	NA NA NA NA	3 JIA did not reach seroprotection No difference in SPR for different treatments No difference in SPR for different vaccine types or schedule
Heijstek et al. [30] Netherlands 2012	400 JIA (NA), 9.4 y (SD 4.5) 93 MTX, 28 steroids, 8 anti-TNF-alpha 2176 healthy (NA), 7.9 y (SD 5.5)	Single-centre, cross-sectional (2C)	Diphtheria and tetanus (Dutch National Institute of Public Health and the Environment/the Dutch Vaccine Institute) NA 6 (4 doses until age 1 y; 4 y; 9 y)	NA	• Lower GMT for diphtheria in JIA (NA, p < 0.01) • Lower GMT for tetanus in JIA (NA, p < 0.01) • Lower SPR for diphtheria in JIA (91 vs 99%, p < 0.01) • Lower SPR for tetanus in JIA (96 vs 99%, p < 0.01)	NA NA NA NA	No difference in GMT between JIA on MTX and JIA on other treatments No difference in GMT between JIA on steroids and JIA without steroids
NA	• Lower GMT for diphtheria in JIA (NA, p < 0.01) • Lower GMT for tetanus in JIA (NA, p < 0.01) • Lower SPR for diphtheria in JIA (77 vs 99%, p < 0.01) • Lower SPR for tetanus in JIA (94 vs 99%, p = 0.01)
Influenza
Camacho-Lovillo et al. [12] Spain 2017	35 JIA (66%), median 10.6 y (IQR 8.8–12.7) 11 etanercept, 4 anakinra, 4 tocilizumab, 4 adalimumab (7 additional MTX), 7 MTX, 2 tocilizumab + MTX + steroids, 3 none 6 healthy (67%), median 11.6 y (IQR 9.8–14.6)	Single-centre, prospective cohort study (2B)	TIV (Sanofi Pasteur MSD) • A/California/7/2009 (H1N1)pdm09 • A/Victoria/361/2011(H3N2) • B/Massachusetts/2/2012 NA 1 (> 9 y), 2 (< 9 y) (0; 1 m)	1–2 m	• No difference in GMT, SCR, SPR for any of the 3 strains between JIA and controls	Whole cohort⁴: local skin inflammation 6 (15%), haematoma 1 (2%) JIA: general malaise and fever > 24 h 1 (3%) Controls: general malaise and fever > 24 h 1 (17%) None JIA: 6 (17%)	No difference in GMT, SCR, SPR for any of the 3 strains for different biologicals or additional steroids
12 m	• No difference in GMT, SCR, SPR for any of the 3 strains between JIA and controls	No difference in GMT, SCR, SPR for any of the 3 strains for different biologicals or additional steroids
Aikawa et al. [22] Brazil 2013	95 JIA (56%), 14.9 y (SD 3.2) 55 steroids, leflunomide, cyclosporine or SSZ, 47 MTX, 16 anti-TNF-alpha¹ 91 healthy (52%), 14.6 y (SD 3.7)	Single-centre, prospective cohort study (2B)	NYMCx-179A (Butantan Institute/Sanofi Pasteur) • A/California/7/2009 (H1N1)pdm09 15 μg 1	21 d	• Lower SCR in JIA (83 (95%CI 76–91) vs 96% (95%CI 91–100), p < 0.01) • No difference in GMT and SPR between JIA and controls	JIA: local pain 20 (21%) Controls: local pain 21 (23%) JIA: myalgia 15 (16%), headache 14 (15%) Controls: headache 18 (20%), myalgia 6 (7%) None None	Lower SCR in JIA with polyarticular disease⁵ compared to controls (80 (95%CI 68–92) vs 96% (95%CI 91–100, p < 0.01) Lower SCR in JIA without anti-TNF-alpha compared to controls (81 (95%CI 72–90) vs 96% (95%CI 91–100), p < 0.05) Lower SPR in JIA without anti-TNF-alpha compared to controls (86 (95%CI 78–94) vs 96% (95%CI 91–100), p < 0.05) No difference in GMT for different treatments
Carvalho et al. [46] Brazil 2013	44 JIA (NA), 11.0 y 31 leflunomide or MTX, 6 steroids, 5 anti-TNF-alpha, 1 cyclosporine 10 healthy (NA), mean NA (range 3.0–18.0)	Single-centre, prospective cohort study (2B)	TIV (Butantan Institute/Sanofi Pasteur SA) • A/Solomon/3/2006(H1N1) • A/Brisbane/10/2007(H3N2) • B/Florida/4/2006 0.25 mL (1–3 y), 0.5 mL (> 3 y) 1 (> 9 y), 2 (< 9 y) (0; 1 m)	30–40 d	• Lower SCR for A/H1N1 strain in JIA (93 vs 100%, p = NA) • Higher SCR for A/H3N2 strain in JIA (74 vs 38%, p = NA) • Higher SCR for B strain in JIA (78 vs 75%, p = NA) • Higher SPR for A/H3N2 strain in JIA (91 vs 80%, p = NA) • Lower SPR for B strain in JIA (95 vs 100%, p = NA) • No difference in SPR for A/H1N1 strain between JIA and controls	JIA: pain 6 (14%), redness and swelling 2 (7%) Controls: pain 1 (10%), redness and swelling 1 (10%) JIA: rhinorrhoea and cough 6 (14%) Controls: None None None	Lower SCR for A/H1N1 strain in JIA on anti-TNF-alpha compared to other treatments (p = 0.03) Lower SPR for A/H1N1 strain in JIA on anti-TNF-alpha compared to other treatments (p = NA) No difference in SPR for A/H3N2 and B strains between JIA on anti-TNF-alpha and controls
Dell’Era et al. [31] Italy 2012	30 JIA (73%), 8.4 y (SD 4.6) 30 MTX or SSZ 30 JIA (47%), 9.5 y (SD 5.7) 30 etanercept 30 healthy (50%), 9.1 y (SD 5.0)	Single-centre, prospective cohort study (2B)	TIV (Novartis) • A/California/7/2009(H1N1)pdm09 • A/Perth/16/2009(H3N2) • B/Brisbane/60/2008 15 μg 1	1 m	• Lower GMT for A/H1N1 strain in JIA on etanercept compared to JIA on MTX and controls (773.6 vs 1833.8 vs 1693.1, p < 0.05) • Lower GMT for B strain in JIA on etanercept compared to JIA on MTX and controls (61.2 vs 187.7 vs 210.6, p < 0.05) • Lower SCR for B strain in JIA on etanercept compared to JIA on MTX and controls (30 vs 83 vs 93%, p < 0.05) • Lower SPR for B strain in JIA on etanercept compared to JIA on MTX and controls (30 vs 83 vs 93%, p < 0.05) • No difference in GMT for A/H3N2 strain between JIA on etanercept, JIA on MTX or SSZ and controls • No difference in SCR and SPR for A/H1N1 and A/H3N2 strains between JIA on etanercept, JIA on MTX or SSZ and controls	JIA on MTX or SSZ: pain 13 (43%), swelling 12 (40%), erythema 2 (7%) JIA on etanercept: pain 11 (37%), swelling 11 (37%), erythema 3 (10%) Controls: pain 12 (40%), swelling 11 (37%), erythema 3 (10%) JIA on MTX or SSZ: rhinitis 9 (30%), changing eating habits 8 (27%), fever 7 (23%), malaise 6 (20%), sleepiness 6 (20%), diarrhoea 2 (7%), vomiting 2 (7%) JIA on etanercept: malaise 8 (27%), rhinitis 8 (27%), changing eating habits 4 (13%), fever 4 (13%), sleepiness 4 (13%), vomiting 2 (7%), diarrhoea 1 (3%) Controls: malaise 8 (27%), rhinitis 7 (23%), changing eating habits 5 (17%), fever 5 (17%), sleepiness 5 (17%), diarrhoea 2 (7%), vomiting 1 (3%) JIA on etanercept: hospitalisation for fever and coxalgia 1 (3%) Controls: none JIA on MTX: 1 (3%)
3 m	• Lower GMT for A/H1N1 in JIA on etanercept compared to JIA on MTX and controls (463.4 vs 1067.7 vs 1324.5, p < 0.05) • Lower GMT for B strain in JIA on etanercept compared to JIA on MTX and controls (33.3 vs 162.6 vs 193.3, p < 0.05) • Lower SCR for B strain in JIA on etanercept compared to JIA on MTX and controls (10 vs 83 vs 90%, p < 0.05) • Lower SPR for B strain in JIA on etanercept compared to JIA on MTX and controls (10 vs 83 vs 90%, p < 0.05) • No difference in GMT for A/H3N2 strain between JIA on etanercept, JIA on MTX or SSZ and controls • No difference in SCR and SPR for A/H1N1 and A/H3N2 strains between JIA on etanercept, JIA on MTX or SSZ and controls
Shinoki et al. [29] Japan 2012	27 JIA (48%), 10.4 y (SD 5.6) 24 steroids + tocilizumab, 3 tocilizumab 17 healthy (47%), 10.6 y (SD 6.2)	Single-centre, prospective cohort study (2B)	TIV (NA) • A/Solomon/3/2006(H1N1) • A/Hiroshima/52/2005(H3N2) • B/Malaysia/2506/2004 0.2 (1–6 y), 0.3 (6–13 y), 0.5 mL (> 13 y) 1 (> 13 y), 2 (< 13 y) (0; 7–28 d)	28–49 d	• No difference in GMT, SCR and SPR for any of the 3 strains between JIA and controls	JIA: local erythema and swelling 3 (11%), local induration 1 (4%) Controls: none JIA: influenza with fever and rhinorrhoea 1 (4%) Controls: none None NA	No difference in GMT for any of the 3 strains between JIA on tocilizumab since ≥ 2 y and JIA on < 0.2 mg/kg steroids No difference in GMT for A/H3N2 and B strains between JIA on > 0.2 mg/kg steroids and JIA on < 0.2 mg/kg steroids
Toplak et al. [28] Slovenia 2012	31 JIA (68%), 11.0 y (SD 4.5, range 3.0–18.0) 18 none, 8 MTX, 3 leflunomide, 2 SSZ, 7 steroids plus MTX, leflunomide or SSZ, 3 etanercept plus MTX, leflunomide or SSZ, 1 infliximab plus MTX, leflunomide or SSZ 14 children with cardiac diseases (29%), 11.9 y (SD 4.5, range 4.0–18.0)	Single-centre, prospective cohort study (2B)	Begrivac 2008/2009^®(Novartis) • A/Brisbane/59/2007(H1N1) • A/Brisbane/10/2007(H3N2) • B/Florida/4/2006 15 μg 1, 2 (< 9 y + 1st dose) (0; 1 m)	1 m	• Lower GMT for A/H1N1 strain in JIA (174.9 vs 240.7, p = NA) • Lower GMT for A/H3N2 strain in JIA (153.2 vs 158.7, p = NA) • Higher GMT for B strain in JIA (100.2 vs 92.2, p = NA) • Lower SCR for A/H1N1, A/H3N2, B strains in JIA (68 vs 79%, p = NA)	JIA: pain 10 (32%) Controls: pain 3 (21%) JIA: malaise and headache 1 (3%) Controls: malaise 2 (14%) None JIA: 11 (35%) 1 m after vaccination 4 2 m after vaccination 1 6 m after vaccination 6	2 JIA and 1 control did not reach seroprotection for A/H1N1 strain 6 JIA and 3 controls did not reach seroprotection for A/H3N2 strain 5 JIA and 3 controls did not reach seroprotection for B strain
6 m	• Higher GMT for A/H1N1 strain in JIA (90.9 vs 72.7, p = NA) • Lower GMT for A/H3N2 strain in JIA (86.3 vs 88.5, p = NA) • Lower GMT for B strain in JIA (98.3 vs 113.5, p = NA) • Lower SCR for A/H1N1, A/H3N2, B strains in JIA (77 vs 79%, p = NA)	Higher GMT for A/H1N1 (105.9 vs 90.9 vs 72.7, p = NA), A/H3N2 (95.4 vs 86.3 vs 88.5, p = NA) and B strains (113.8 vs 98.3 vs 113.5, p = NA) in JIA on MTX, leflunomide or SSZ compared to JIA on other treatments and controls
Meningococcus C
Stoof et al. [20] Netherlands 2014	127 JIA (62%), 8.9 y (SD 3.7) 108 MTX, 44 etanercept, 14 steroids, 6 infliximab, 9 anakinra, 1 anti-IL-6 1527 healthy (54%), 9.1 y (SD 5.1)	Single-centre, retrospective cohort study (2B)	NeisVac-C^®(Baxter Healthcare) 19 μg (N. meningitidis serogroup C polysaccharide strain C11), 10–20 μg (tetanus toxoid) 1	50 m	• No difference in GMT between JIA and controls	NA NA NA NA	No difference in GMT decrease in JIA starting MTX treatment during the study
Zonneveld-Huijssoon et al. [26] Netherlands 2007	234 JIA (65%), 11.1 y (SD 4.2, range 1.5–18.9) Group I: 47 none Group II: 41 NSAID Group III: 36 MTX, 7 SSZ Group IV: 15 MTX, 6 etanercept, 2 infliximab, 2 MTX + SSZ, 1 cyclosporine	Multicentre, prospective cohort study (2B)	NeisVac-C^®(NA) 20 μg/mL (N. meningitides Z2491 serogroup C polsysaccharide), 20–40 μg/mL (tetanus toxoid) 1	< 3 m	• Lower GMT in group III and IV compared to group I and II (17.5 vs 16.3 vs 41.0 vs 46.9 μg/mL, p ≤ 0.01) • No difference in GMT between group III and group IV	NA NA NA None	Low GMT (< 2 µg/mL) in 4 JIA (2 on etanercept + MTX, 1 on MTX, 1 on SSZ)
Pneumococcus
Aikawa et al. [19] Brazil 2015	17 JIA (47%), median 11.6 y 17 etanercept, 16 MTX, 6 steroids, 4 cyclosporine, 4 leflunomide¹ 10 JIA (40%), median 9.2 y 10 MTX, 1 cyclosporine¹	Single-centre, prospective cohort study (2B)	Pneumovax^®(Sanofi Pasteur) NA 1	2 m	• No difference in GMT, SCR, SPR for serotypes 4, 6B, 9 V, 14, 18C, 19F, 23F between JIA on etanercept and controls	JIA on etanercept: none Controls: swelling and redness 1 (10%) JIA on etanercept: upper respiratory tract infection requiring antibiotics 11 (65%) Controls: upper respiratory tract infection requiring antibiotics 3 (30%) JIA on etanercept: invasive pneumococcal disease with a bacterial pneumonia requiring hospitalization 1 (6%) Controls: none None
12 m	• No difference in GMT, SCR, SPR for serotypes 4, 6B, 9 V, 14, 18C, 19F, 23F between JIA on etanercept and controls
Farmaki et al. [38] Greece 2010	31 JIA (68%), 12.9 y (SD 4.6) 26 MTX, 21 etanercept, 10 adalimumab, 8 steroids, 5 cyclosporine¹ 32 JIA (78%), 11.6 y (SD 3.3) 26 MTX, 8 steroids, 7 cyclosporine¹	Single-centre, prospective cohort study (2B)	Prevenar^®(NA) NA 2 (0; 42–56 d)	Mean 42 d (SD 3.3) after 1st dose	• Lower GMT for serotypes 4 (1.8 vs 5.0 μg/mL, p < 0.01), 14 (5.5 vs 10.3 μg/mL, p = 0.01) and 23F (4.5 vs 11.2 μg/mL, p = 0.02) in JIA on etanercept or adalimumab • No difference in SPR for serotypes 4, 6 V, 9 V, 14, 18C, 19F, 23F	JIA on etanercept or adalimumab 6 (19%): pain, redness, swelling Controls 5 (16%): pain, redness, swelling None None JIA on etanercept or adalimumab: 1 (3%)	No difference in GMT and SPR for JIA on adalimumab compared to JIA on etanercept
Mumps, measles, rubella
Heijstek et al. [45] Netherlands 2013	Group 1: 63 JIA (73%), 6.3 y (95%CI 5.9–6.7) 29 MTX, 5 etanercept, 3 anti-IL-1, 2 steroids, 1 adalimumab, 1 leflunomide¹ Group 2: 68 JIA (60%), 6.5 y (95%CI 6.2–6.9) 31 MTX, 4 etanercept, 1 anti-IL-1, 1 leflunomide, 1 steroids¹	Multicentre, non-blinded, controlled, randomised trial (1B)	MMR-NV1^®(Netherlands vaccine Institute) or M-M-RVAXPRO^®(Sanofi Pasteur) NA 1 MMR booster in group 1	12 m	• Higher GMT for measles in JIA with MMR booster (1.6 vs 0.8 IU/mL, p = 0.03) • Higher GMT for mumps in JIA with MMR booster (168.0 vs 104.0 RU/mL, p = 0.03) • Higher GMT for rubella in JIA with MMR booster (69.0 vs 45.0 IU/mL, p = 0.01) • Higher SPR for measles in JIA with MMR booster (100 vs 92% (95%CI 84–99), p = ns) • Higher SPR for mumps in JIA with MMR booster (97 (95%CI 95–100) vs 81% (95%CI 72–93), p = ns) • Higher SPR for rubella in JIA with MMR booster (100 vs 94% (95%CI 86–100), p = ns)	NA Group 1: abdominal pain and/or obstipation 4 (6%), bone fracture due to trauma 4 (6%), upper respiratory tract infection 4 (6%), arthralgia 3 (5%), contusion due to trauma 3 (5%), gastroenteritis 3 (5%), otitis 3 (5%), rash 3 (5%), eczema 2 (3%), fever 2 (3%), molluscum contagiosum 2 (3%), bronchopneumonia 1 (2%), CRP elevation 1 (2%), fungal infection 1 (2%), headache 1 (2%), varicella infection 1 (2%), worsening of pre-existent anxiety attacks 1 (2%) Group 2: contusion due to trauma 4 (6%), gastroenteritis 4 (6%), abdominal pain and/or obstipation 3 (4%), rash 3 (4%), upper respiratory tract infection 3 (4%), viral infection 3 (4%), eczema 2 (3%), myalgia 2 (3%), A/H1N1 infection 1 (1%), fever 1 (1%), headache 1 (1%), impetigo 1 (1%), molluscum contagiosum 1 (1%), vaginal discharge 1 (1%), watery discharge from the eyes 1 (1%) Group 1: hospital admissions 3 (5%), surgery 2 (3%) Group 2: surgery 6 (9%), hospital admission 5 (7%) None	No difference in GMT at 3 and 12 m in JIA on MTX and JIA on other treatments 5 controls were not seroprotected for measles 2 JIA (1 on MTX, 1 on MTX + etanercept) and 12 controls did not reach seroprotection for mumps 4 controls did not reach seroprotection for rubella
Heijstek et al. [30] Netherlands 2012	400 JIA (NA), 9.4 y (SD 4.5) 93 MTX, 28 steroids, 8 anti-TNF-alpha (NA)¹ 2176 healthy (NA), 7.9 y (SD 5.5)	Single-centre, cross-sectional study (2C)	MMR (Dutch National Institute of Public Health and the Environment/the Dutch Vaccine Institute) NA 2 (age 14 m and 9 y)	NA	• Higher GMT for measles in JIA (NA, p < 0.01) • Lower GMT for mumps in JIA (NA, p < 0.01) • Lower GMT for rubella in JIA (NA, p < 0.01) • Higher SPR for measles in JIA (94 vs 87%, p = 0.01) • No difference in SPR for mumps between JIA and controls • No difference in SPR for rubella between JIA and controls	NA NA NA NA	Higher GMT for measles (p = 0.02) in JIA with high disease activity No difference in GMT between JIA on MTX and JIA on other treatments No difference in GMT between JIA on steroids and JIA without steroids
Monovalent measles (NA) vaccine plus MMR (NA) or rubella (Dutch National Institute of Public Health and the Environment) NA 2 (age 14 m and 4 y or 11 y)	NA	• Higher GMT for measles in JIA (NA, p < 0.01) • Lower GMT for mumps in JIA (NA, p < 0.01) • Lower GMT for rubella in JIA (NA, p < 0.01) • Lower SPR for mumps in JIA (81 vs 95%, p < 0.01) • Lower SPR for rubella in JIA (81 vs 99%, p < 0.01) • No difference in SPR for measles between JIA and controls
Borte et al. [14] Germany 2009	15 JIA (NA) Group I: 5 MTX start > 4 y after MMR, 15.8 y (range 14.2–17.9) Group II: 5 MTX ≥ 6 m before MMR, 6.7 y (range 6.6–6.7) Group III: 5 etanercept + MTX ≥ 6 m before MMR, 6.3 y (range 6.0–6.7) Group IV: 22 healthy (NA), 11.2 y (range 1.0–20.0)	Single-centre, prospective nested case–control study (3B)	MMR (NA) NA 2 (age 13–24 m and 6 y)	Group I: 6 m after MTX start	• Lower GMT for measles in JIA (group I) compared to healthy children (group V) (194.3 (IQR 0.0–410.0) vs. 1231.7 IU/mL (IQR 461.0–1730.0), p < 0.05) • No difference in GMT for mumps between JIA (group I) and controls • No difference in GMT for rubella between JIA (group I) and controls	NA NA NA None
Group II, III, IV: 6 m after vaccination	• No difference in GMT for measles, mumps and rubella between JIA (group II, III) and controls (group IV)
Systemic lupus erythematosus (SLE)
Hepatitis B
Aytac et al. [34] Turkey 2011	20 SLE (80%), 13.2 y (SD 2.6, range 9.1–19.8) 17 steroids, 11 azathioprine, 3 mycophenolate mofetil, 3 none, 2 hydroxychloroquine¹ 24 healthy (50%), 8.8 y (SD 2.7, range 5.0–14.0)	Single-centre, prospective cohort study (2B)	Engerix-B^®(GlaxoSmithKline) 10 μg (weight < 20 kg), 20 μg (weight > 20 kg) 3 (0; 1; 6 m)	1 m	• Lower GMT in SLE (310.4 (range 0.0–500.0) vs 618.5 IU/mL (range 70.0–900.0), p = NA) • No difference in SPR between SLE and controls	None None None SLE: 3 (15%)
Tetanus
Miyamoto et al. [36] Brazil 2011	20 inactive SLE (85%), 14.0 (SD 2.0; range 10.0–17.0) 17 chloroquine, 14 steroids, 8 azathioprine, 2 cyclosporine, 2 MTX, 1 mycophenolate mofetil¹ 10 active SLE (90%), 12.0 (SD 2.0; range 8.0–14.0) 14 steroids, 8 chloroquine, 6 azathioprine, 2 cyclophosphamide¹ 14 healthy (71%), 14.0 y (SD 3.0, range: 8.0–18.0)	Single-centre, retrospective case–control (3B)	DTP (NA) NA 5 (age 2, 4, 6, 15 m and 4–6 y)	NA	• Lower GMT in inactive SLE (0.14 vs 0.68 IU/mL, p < 0.05) • No difference in GMT between active SLE and controls	NA NA NA NA
Kashef et al. [15] Iran 2008	40 SLE (80%), 14.1 y (range 7.0–21.0) 13 azathioprine + steroids, 10 cyclophosphamide + steroids, 8 mycophenolate mofetil + steroids, 5 azathioprine + cyclophosphamide + steroids 60 healthy (69%), 14.4 y (range NA)	Multicentre, retrospective case–control study (3B)	Tetanus (NA) NA 5 (until age 6 y)	NA	• No difference in GMT between SLE and controls	NA NA SLE: disseminated infections requiring hospital admission 4 (10%) Controls: none NA
Influenza
Campos et al. [21] Brazil 2013	118 SLE (77%), 16.0 y (SD 3.5) 92 antimalarials, 83 steroids, 44 azathioprine, 15 mycophenolate mofetil, 14 MTX, 3 cyclophosphamide, 2 cyclosporine¹ 102 healthy (50%), 15.9 y (SD 4.5)	Single-centre, prospective cohort study (2B)	NYMCX-179A (Butantan Institute/Sanofi Pasteur) • A/California/7/2009(H1N1) pdm09 15 μg 1	21 d	• Lower GMT in SLE (90.8 (95%CI 67.8–121.7) vs 237.3 NA (95%CI 188.8–298.3), p < 0.01) • Lower SCR in SLE (64 (95%CI 54–72) vs 91% (95%CI 84–96), p < 0.01) • Lower SPR in SLE (74 (95%CI 65–81) vs 95% (95%CI 89–98), p < 0.01)	SLE: itching 20 (17%), redness 13 (11%) Controls: redness 2 (2%) SLE: arthralgia 20 (17%), rhinorrhoea 15 (13%) Controls: rhinorrhoea 4 (4%), arthralgia 1 (1%) None None	Children with SLE on higher steroid doses (18.0 mg/d (SD 21.4)) did more frequently not seroconvert than children with SLE on lower doses (10.5 mg/d (SD 12.5)) Lower frequency of renal involvement in SLE 4 m after-vaccination compared to baseline (28 vs 51%, p < 0.01) Higher frequency of mucocutaneous lesions in SLE 4 m after-vaccination compared to baseline (17 vs 6%, p = 0.02)
Measles
Miyamoto et al. [36] Brazil 2011	20 inactive SLE (85%), 14.0 (SD 2.0; range 10.0–17.0) 17 chloroquine, 14 steroids, 8 azathioprine, 2 cyclosporine, 2 MTX, 1 mycophenolate mofetil¹ 10 active SLE (90%), 12.0 (SD 2.0; range 8.0–14.0) 14 steroids, 8 chloroquine, 6 azathioprine, 2 cyclophosphamide¹ 14 healthy (71%), 14.0 y (SD 3.0, range: 8.0–18.0)	Single-centre, retrospective case–control (3B)	Measles (NA) NA 2 (after age 2 y)	NA	• No difference in GMT between active SLE, inactive SLE and controls	NA NA NA NA	Lower IgM titres in inactive SLE (1.2 vs 1.7 g/l, p = 0.03) No difference in IgA and IgG titres between active and inactive SLE and controls
Varicella
Barbosa et al. [47] Brazil 2012	28 SLE (75%), 15.3 y (SD 2.5, range 9.9–18.8) 27 chloroquine, 18 steroids, 9 azathioprine, 2 MTX¹ 28 healthy (75%), 15.0 y (SD 2.5, range 10.1–18.7)	Multicentre, blinded, controlled, randomised trial (1B)	Oka strain (Biken) > 10³ PFU 1	1 m	• No difference in GMT between SLE and controls	SLE 2 (7%): NA Controls 6 (21%): NA SLE: headache 10 (36%), fever 3 (11%), rash 1 (4%) Controls: headache 6 (21%), fever 4 (14%), vomiting 1 (4%), rash 1 (4%) None None
6 m	• No difference in GMT between SLE and controls
12 m	• No difference in GMT between SLE and controls
Juvenile autoimmune rheumatic disease (JARD)
Hepatitis A and B
Belderok et al. [17] Netherlands 2013	78 JARD (71 JIA, 2 SLE, 2 uveitis, 1 autoinflammatory syndrome, 1 JDM, 1 panuveitis) (64%), median 12.0 y (IQR 9.0–14.0) 42 MTX, 24 MTX + anti-TNF-alpha (adalimumab, etanercept or infliximab), 2 MTX + anti-TNF-alpha + steroids, 4 anti-TNF-alpha, 1 anakinra, 1 anti-TNF-alpha + cyclosporine, 1 azathioprine, 1 cyclosporine, 1 MTX + anakinra, 1 MTX + steroids, 1 mycophenolate mofetil, 1 mycophenolate mofetil + steroids	Multicentre, prospective cohort study (2B)	Ambirix^®(GlaxoSmithKline) 720 ELISA units (HAV), 20 μg (hepatitis B surface antigen) 2 (0; 6–7 m)	35 d	• GMT for HAV in JARD (288.0 mIU/mL) • GMT for HBV in JARD (321.0 mIU/mL) • Positive SCR for HAV in JARD (100% (95%CI 96–100)) • Positive SCR for HBV in JARD (93% (95%CI 86–98))	NA NA NA NA	No difference in GMT for different treatments
Human papillomavirus
Heijstek et al. [48] Netherlands 2013	12 JARD (6 JDM, 6 SLE) (100%) age JDM vs SLE 15.3 (SD 2.3) vs 15.0 (SD 1.5) 6 steroids, 5 none, 2 hydroxychloroquine, 2 MTX, 1 azathioprine, 1 mycophenolate mofetil¹ 49 healthy (100%), 14.3 y (SD 1.2)	Single-centre, prospective cohort study (2B)	Cervarix^®(GlaxoSmithKline) NA 3 (0; 1; 6 m)	1 m	• Lower GMT for HPV16 (NA, p < 0.01) and HPV18 (NA, p = 0.04) in JARD	NA NA NA JDM 1 (17%)	1 JDM did not seroconvert (without immunosuppressive drugs)
6 m	• No difference in GMT between JARD and controls
Tetanus
Ingelman-Sundberg et al. [40] Sweden 2016	50 JARD (46 JIA, 1 erythema nodosum with arthritis, 1 JDM, 1 mixed connective tissue disease, 1 polyarteritis nodosa) (64%) median age: JARD on MTX 12.2 y (range 6.0–16.0); anti-TNF-alpha + MTX 13.1 y (range 2.9–18.3); no treatment 13.8 y (range 4.3–16.0) 15 etanercept, 10 MTX, 8 adalimumab + MTX, 8 none, 7 infliximab + MTX, 2 golimumab + MTX (some on additional steroids) 31 healthy (32%), median 11.5 y (range 2.4–17.7)	Single-centre, cross-sectional study (2C)	DTP (NA) NA ≥ 3 doses⁶	NA	• Lower GMT for tetanus following booster in JARD on anti-TNF-alpha + MTX or MTX compared to JARD without treatment and healthy controls (NA, p = 0.02) • No difference in GMT for tetanus following booster for different treatments in JARD	NA NA NA NA	Lower transition B cell proportions in JARD (NA, p < 0.01) Lower transition B cell proportions in JARD on anti-TNF-alpha compared to JARD without anti-TNF-alpha and controls (NA, p < 0.01)
Influenza
Aikawa et al. [18] Brazil 2013	38 JARD (25 JIA, 5 JDM, 3 JScle, 3 SLE, 2 vasculitis) (76%), median 7.0 y (range 2.6–9.0) 23 MTX, 12 steroids, 7 anti-TNF-alpha, 6 cyclosporine, 5 none, 1 azathioprine, 1 leflunomide¹ 11 healthy (64%), median 7.8 y (range 3.2–8.9)	Single-centre, prospective cohort study (2B)	NA (Butantan Institute/Sanofi Pasteur) • A/California/7/2009(H1N1) pdm09 15 μg 2 (0; 21 d)	NA	• No difference in GMT, SCR and SPR between JARD and controls	JARD: pain 4 (11%) Controls: pain 2 (18%) JARD: headache 6 (16%), cough 4 (11%), fever 4 (11%), malaise 3 (8%), myalgia 2 (5%), rhinorrhoea 2 (5%), arthralgia 1 (3%) Controls: fever 1 (9%) None None	7 JARD (6 JIA, 1 SLE) did not seroconvert
Aikawa et al. [32] Brazil 2012	237 JARD (99 SLE, 93 JIA, 18 JDM, 11 JScle, 16 primary vasculitis) (66%), 14.8 y (SD 3.0) 90 steroids, 74 MTX, 43 azathioprine, 23 cyclosporine, 13 mycophenolate mofetil, 6 leflunomide, 3 cyclophosphamide¹ 91 healthy (52%), 14.6 y (SD 3.7)	Single-centre, prospective cohort study (2B)	NYMCx-179A (Butantan Institute/Sanofi Pasteur) • A/California/7/2009(H1N1) pdm0915 μg	21 d	• Lower GMT in JARD (147.2 (95%CI 119.7–181.1) vs 250.8 IU/mL (95%CI 196.3–320.3), p = 0.01) • Lower SCR in JARD (74 (95%CI 69–80%) vs 96% (95%CI 91–100%), p < 0.01) • Lower SPR in JARD (81 (95%CI 77–86%) vs 96% (95%CI 91–100%), p < 0.01)	JARD: pain 43 (18%), itching 19 (8%), redness 9 (4%), swelling 3 (1%) Controls: pain 21 (23%), redness 21 (23%), swelling 2 (1%) JARD: headache 41 (17%), arthralgia 31 (13%), myalgia 27 (11%), rhinorrhoea 19 (8%), cough 16 (7%), fever 13 (6%), nasal congestion 13 (6%), sore throat 9 (4%), diarrhoea 8 (3%) Controls: headache 18 (20%), myalgia 6 (7%), cough 5 (6%), sorethroat 5 (6%), fever 3 (3%), nasal congestion 3 (3%), rhinorrhoea 3 (3%), arthralgia 2 (2%), diarrhoea 2 (2%) None None	Lower GMT in SLE compared to controls (91.1 (95%CI 66.0–125.8) vs 250.8 IU/mL (95%CI 196.3–320.3), p > 0.05) Lower GMT in JARD on azathioprine (NA, p = 0.02) and mycophenolate mofetil (NA, p = 0.01) compared to JARD on other treatments Lower SCR in SLE (64% (95%CI 54–73), p < 0.01), JIA (83% (95%CI 75–91), p = 0.01), JDM (78% (95%CI 59–97), p = 0.03) and primary vasculitis (75 (95%CI 54–96), p = 0.02) compared to controls (96% (95%CI 91–100%) Lower SCR in JARD on steroids compared to JARD without steroids (60 vs 83%, p < 0.01) Lower SCR in JARD on immunosuppressive drugs and steroids compared to JARD without immunosuppressive drugs and steroids (65 vs 78%, p = 0.04) Lower SPR in SLE compared to controls (73.7 (95%CI 65.0–82.4 vs 96% (95%CI 91–100%), p < 0.01)
Woerner et al. [33] Switzerland 2011	36 JARD (25 JIA, 3 uveitis, 2 inflammatory bowel disease, 2 chronic recurrent multifocal osteomyelitis, 1 JDM, 1 vasculitis, 1 SLE, 1 mixed connective tissue disease) (64%), median 13.8 y (range 2.3–16.0) 18 MTX, 10 anti-TNF-alpha, 8 anti-TNF-alpha + MTX 16 children with diabetes mellitus or cystic fibrosis (50%), median 11.9 y (7.8–15.1)	Single-centre, prospective cohort study (2B)	Inflexal V^®(Crucell Switzerland) 2007/2008 • A/Solomon/3/2006(H1N1) • A/Wisconsin/67/2005(H3N2) • B/Malaysia/2506/2004 2008/2009 • A/Brisbane/59/2007(H1N1) • A/Brisbane/10/2007(H3N2) • B/Florida/4/2006 7.5 μg (> 3 y) or 15 μg (< 3 y + 1st dose) 1, 2 (< 3 y + 1st dose) (0; 1 m)	1–2 m	• No difference in GMT, SCR and SPR for any of the 3 strains between JARD and controls	JARD: pain or tenderness 5 (14%) Controls: pain or tenderness 2 (13%) JARD: fever, headache or myalgia 4 (12%) Controls: fever, headache or myalgia 1 (7%) None NA	No difference GMT, SCR and SPR for different treatments
Ogimi et al. [37] Japan 2011	49 JARD (23 JIA, 12 SLE, 6 JDM, 2 mixed connective tissue disease, 2 Kawasaki, 2 Takayasu arteritis, 1 Crohn’s disease, 1 Wegener granulomatosis) (71%), 12.1 y (SD 4.8) 14 steroids, 7 MTX + steroids, 7 mycophenolate mofetil + steroids, 6 cyclosporine + MTX + steroids, 2 azathioprine + steroids, 2 cyclosporine, 2 mizoribine + steroids, 1 azathioprine + cyclosporine + MTX, 1 azathioprine + cyclosporine + steroids, 1 azathioprine + mizoribine + steroids, 1 azathioprine + MTX + steroids, 1 cyclosporine + mizoribine + steroids, 1 cyclosporine + mycophenolate mofetil + steroids, 1 infliximab + MTX + steroids, 1 MTX, 1 MTX + tacrolimus + steroids 36 healthy (36%), 8.6 y (SD 14.3)	Single-centre, prospective cohort study (2B)	TIV (Kaketsuken, BIKEN) • A/H1N1 (NA) • A/H3N2 (NA) • B (NA) 0.1 (< 1 y), 0.2 (1–5 y), 0.3 (6–12 y), 0.5 mL (> 13 y) 2 (7–28 d)	14–28 d	• Higher GMT for B strain in JARD⁷ (60.3 vs 23.8, p < 0.01) • No difference in GMT for A/H1N1 and A/H3N2 strain between JARD and controls • No difference in SCR for any of the 3 strains between JARD and controls	JARD: pain and swelling 1 (2%) Controls: pain and/or swelling 3 (8%) None None JARD 2 (4%)
Kanakoudi–Tsakalidou et al. [27] Greece 2001	70 JARD (49 JIA, 11 SLE, 3 JDM, 3 systemic vasculitis, 2 connective tissue disease, 1 Behçet’s disease, 1 idiopathic recurrent pericarditis) (73%), 11.6 y (SD 4.5) 16 MTX + steroids, 16 steroids, 11 cyclosporine + steroids, 8 cyclosporine + MTX + steroids, 6 azathioprine + steroids, 5 MTX, 4 cyclosporine, 4 cyclosporine + MTX	Single-centre, prospective case series (4)	Fluarix^®SB (NA) • A/Beijing/262/95(H1N1) • A/Sydney/5/97(H3N2) • B/Beijing/184/93 NA 1, 2 (4–8 y and low pre-vaccination GMT) (0; 1 m)	1 m	• GMT for A/H1N1 (492.0), A/H3N2 (1449.0) and B strains (112.0) in JARD • SPR for A/H1N1 (97%), A/H3N2 (100%) and B strains (80%) in JARD • No difference in GMT and SPR for any of the 3 strains between JIA and SLE • No difference in GMT and SPR for any of the 3 strains for different treatments	JARD: 3 pain (4%), redness 1 (1%) JARD: fever and convulsion 1 (1%)⁸, sore throat and cough 1 (1%) None None	Higher increase in seroprotection for A/H1N1 compared to B strain after the 2nd vaccination in JARD with non-protective titre prior to 2nd vaccination (68% vs 5% (p < 0.01)) 15 JARD (13 JIA, 1 SLE, 1 systemic vasculitis) did not reach seroprotection
Measles, rubella
Ingelman-Sundberg et al. [40] Sweden 2016	50 JARD (46 JIA, 1 erythema nodosum with arthritis, 1 JDM, 1 mixed connective tissue disease, 1 polyarteritis nodosa) (64%) median age JARD on MTX vs anti-TNF-alpha + MTX vs none 12.2 y (range 6.0–16.0) vs 13.1 y (range 2.9–18.3) vs 13.8 y (range 4.3–16.0) 15 etanercept, 10 MTX, 8 adalimumab + MTX, 8 none, 7 infliximab + MTX, 2 golimumab + MTX (some on additional steroids) 31 healthy (32%), median 11.5 y (range 2.4–17.7)	Single-centre, cross-sectional study (2C)	MMR (NA) NA ≥ 1 doses⁶ (1st dose before age 18 m)	NA	• No difference in GMT for measles and rubella between JARD with/without booster and healthy with/without booster	NA NA NA NA	Lower transition B cell proportions in JARD (NA, p < 0.01) Lower transition B cell proportions in JARD on anti-TNF-alpha compared to JARD without anti-TNF-alpha and controls (NA, p < 0.01) Low avidity range for rubella in 1 JARD (NA, p = 0.02)⁹
Varicella
Speth et al. [24] Germany 2018	14 JARD (11 JIA, 2 JDM, 1 microscopic polyangiitis) on HIIS (71%), median 9.7 y (range 2.7–17.8) 2 etanercept, 2 MTX, 1 abatacept + leflunomide, 1 adalimumab + MTX, 1 anakinra + leflunomide + steroids, 1 anakinra + MTX + steroids, 1 etanercept + leflunomide + steroids, 1 etanercept + steroids, 1 leflunomide, 1 leflunomide + tocilizumab, 1 MTX + tocilizumab, 1 mycophenolate mofetil 9 JIA on LIIS (89%), median 8.3 y (range 1.8–17.8) 9 MTX	Single-centre, prospective cohort study (2B)	Varilrix^®(GlaxoSmithKline) 10^3.3 PFU 2 (42 d (LIIS), 3 m (HIIS))	1–3 m	• No difference in GMT between JARD on HIIS and JARD on LIIS	JARD on HIIS 1 (7%): NA JARD on LIIS 1 (11%): NA JARD on HIIS: arthralgia 1 (7%), elevated temperature 1 (7%), headache 1 (7%), vomiting 1 (7%) JARD on LIIS: arthralgia 3 (33%) None None	Low IgG levels (< 200 mIU/mL) in 2 JARD (1 on mycophenolate mofetil, 1 on leflunomide and abatacept) after 2nd vaccination
Groot et al. [25] Netherlands 2017	49 JARD (39 JIA, 5 JDM, 5 JScle) (53%) 1 vs 2 doses 5.0 y (range 2.0–15.0) vs 3.5 y (range 2.0–17.0) 25 MTX, 16 MTX + steroids, 2 cyclosporine + MTX, 2 leflunomide + MTX, 1 abatacept + MTX, 1 adalimumab + MTX, 1 azathioprine + MTX, 1 etanercept + MTX, 1 MTX + penicillamine 18 healthy (50%) median 8.5 y (range 3.0–18.0)	Single-centre, prospective cohort study (2B)	Oka strain (Biken) > 10³ PFU 1 if 2nd dose: Varilrix® (NA) 10^3.3 PFU 1	28–42 d after 1st dose	• No difference in GMT between JIA, JDM or JScle and controls	None JIA: elevated temperature (< 38 °C) and vesicular rash 2 (3%) JScle: elevated temperature (< 38 °C) and vesicular rash 1 (20%) Controls: fever 1 (6%) None JIA: 3 (8%)	1 JARD (on abatacept) did not reach seroprotection after 2nd dose Higher GMT in JARD with 2 doses compared to JARD and controls with 1 dose (NA, p < 0.01) No difference in GMT for different treatments
12 m after 1st dose	• No difference in GMT between JIA, JDM, JScle and controls
Pileggi et al. [39] 2010 Brazil	25 JARD (17 JIA, 4 JDM, 2 JScle, 1 vasculitis) (52%), median 7.2 y (range 2.0–19.0) 12 MTX, 8 MTX + steroids, 3 cyclosporine + MTX + steroids, 1 leflunomide + MTX + steroids, 1 MTX + penicillamine + steroids 18 healthy (NA), median 9.3 y (range 3.0–18.0)	Single-centre, prospective cohort study (2B)	Oka strain (NA) 0.5 mL 1	28–42 d	• No difference in GMT and SPR between JARD and controls	None JARD: fever 1 (4%), rash 3 (12%) Controls: fever 1 (6%) None None	2 JARD who did not reach seroprotection developed varicella
12 m	• SPR in JARD (80%)

Author
Country
Publication year

Number of participants (% female), mean age (unless otherwise specified)
Treatment
Number of controls (% female), mean age (unless otherwise specified)
Treatment (if any)

Study type (Level of evidence)

Vaccine (producer)
Dosage
Number of doses (interval)

Timing of blood sampling after last vaccination

Immunogenicity

Local reactions
Systemic reactions
Severe adverse events
Worsening in disease activity

Additional findings

Enthesitis-related arthritis (ERA)

Measles, rubella

Maritsi et al. [43]

Greece

2019

41 ERA (25%), 11.7 y (SD 4.3)

41 adalimumab initiated after vaccination, 25 MTX, 6 SSZ¹

149 healthy, 11.8 y (SD 3.7)

Single-centre, prospective cohort study (2B)

Measles (NA)

2 (age 2 y and 5 y)

Rubella (NA)

2 (age 2 y and 5 y)

12 m²

• Lower GMT for measles in ERA (190.0 (95%CI 138.0–264.0) vs 256.0 IU/mL (95%CI 159.0–294.0), p = 0.04)

• Lower GMT for rubella in ERA (29.9 (95%CI 23.2–38.5) vs 41.6 IU/mL (95%CI 35.0–46.0), p < 0.01)

• No difference in SPR for measles and rubella between ERA and controls

No difference in GMT and SPR for measles and rubella for children who were only on adalimumab or on additional MTX or SSZ

36 m²

• Lower GMT for measles in ERA (167.0 (95%CI 124.0–256.0) vs 251.0 IU/mL (95%CI 107.0–264.0), p = 0.02)

• Lower GMT for rubella in ERA (26.2 (95%CI 20.2–33.9) vs 41.0 IU/mL (95%CI 32.0–46.0), p < 0.01)

• No difference in SPR for measles and rubella between ERA and controls

No difference in GMT and SPR for measles and rubella for children who were only on adalimumab or on additional MTX or SSZ

Juvenile dermatomyositis (JDM)

Human papillomavirus

Grein et al. [42]

Brazil

2020

42 JDM (100%), median 16.0 y (IQR 13.0–19.0)

20 steroids, 17 hydroxychloroquine, 15 MTX, 11 none, 8 azathioprine, 7 cyclosporine, 2 IVIG, 1 mycophenolate mofetil¹

35 healthy (100%), median 14.0 y (IQR 6.5–21.5)

Multicentre, prospective cohort study (2B)

Gardasil^®(NA)

3 (0; 1 m or 2 m; 6 m)

1 m

• No difference in SPR for HPV16 and HPV18 between JDM and controls

JDM: pain 57 (47%), induration 14 (12%), oedema 10 (8%), redness 7 (6%), bruise 1 (1%)

Controls: pain 65 (59%), oedema 21 (19%), induration 18 (16%), redness 9 (8%), bruise 6 (5%)³

JDM: headache 25 (21%), fatigue 14 (12%), nausea 12 (10%), itchiness 11 (9%), muscular pain 4 (3%), new cutaneous abnormalities 4 (3%), articular pain 2 (2%), fever 2 (2%), vomiting 2 (2%)

Controls: headache 27 (24%), fatigue 19 (17%), nausea 7 (6%), itchiness 2 (2%), muscular pain 2 (2%), fever 1 (1%)³

None

JDM: 1 (2%)

No difference in SPR for HPV18 for different treatments

2 JDM (1 on MTX, 1 on hydroxychloroquine + steroids) did not reach seroprotection for HPV16 and HPV18

1 JDM (on azathioprine + hydroxychloroquine + steroids) did not reach seroprotection for HPV18

6 m

• SPR for HPV16 and HPV18 94% in JDM, values in controls NA

No difference in SPR for HPV16 and HPV18 for different treatments

1 JDM (on azathioprine + hydroxychloroquine + steroids) did not reach seroprotection for HPV 18

Influenza

Guissa et al. [23]

Brazil

2012

30 JDM (63%), median 15.5 y (range 9.0–21.0, 7 children ≤ 18 y)

15 steroids, 14 MTX, 6 cyclosporine, 2 azathioprine, 7 chloroquine¹

81 healthy (41%), median 15.0 y (range 9.0–21.0)

Single-centre, prospective cohort study (2B)

NYMCx-179A (Butantan Institute/Sanofi Pasteur)

• A/California/7/2009(H1N1)pdm09

15 μg

21 d

• Lower SCR in JDM (87 (95%CI 75–99) vs 98% (95%CI 94–100), p = 0.04)

• No difference in GMT and SPR between JDM and controls

JDM: pain 9 (30%)

Controls: pain 19 (23%), swelling 2 (2%), redness 2 (2%), itching 1 (1%)

JDM: headache 5 (17%), rhinorrhoea 4 (13%), arthralgia 1 (3%), fever 1 (3%), myalgia 1 (3%)

Controls: headache 18 (22%), myalgia 6 (7%), cough 5 (6%), sore throat 5 (6%), fever 3 (4%), rhinorrhoea 3 (4%), nasal congestion 3 (4%), arthralgia 2 (2%), diarrhoea 2 (2%)

None

4 JDM did not reach seroprotection

Juvenile idiopathic arthritis (JIA)

Hepatitis A

Maritsi et al. [13]

Greece

2017

83 JIA (66%), 6.3 y (SD 2.3)

83 MTX

76 healthy (45%), 5.3 y (SD 2.7)

Single-centre, prospective cohort study (2B)

Havrix^®(GlaxoSmithKline)

720 IU/mL

2 (0; > 6 m)

1 m

• Lower GMT in JIA (94.0 vs 162.5 mIU/mL, p < 0.01)

• No difference in SCR and SPR between JIA and controls

JIA: 5 (6%)

Controls: 4 (5%)

JIA: fever 3 (4%), malaise 3 (4%)

Controls: fever 2 (3%), malaise 2 (3%)

None

JIA: 15 (18%) (in 2 after the 1st dose and in 13 after the 2nd dose after a mean of 8 months)

No difference in GMT, SCR and SPR between different JIA subtypes (ERA, oligoarticular JIA with, polyarticular JIA, psoriatic JIA)

No difference in GMT, SCR and SPR in JIA with or without presence of uveitis or ANA positivity

12 m

• Lower GMT in JIA (98.2 vs 200.3 mIU/mL, p < 0.01)

• No difference in SCR and SPR between JIA and controls

Erguven et al. [35]

Turkey

2011

47 JIA (51%), 10.7 y (SD 3.9)

19 SSZ, 18 MTX, 11 MTX + steroids, 4 etanercept, 1 steroids¹

67 healthy (46%), 9.4 y (SD 3.8)

Single-centre, prospective cohort study (2B)

Hepatitis A (NA)

2 (0; 6 m)

2 m

• Lower SPR in JIA (92 vs 100%, p < 0.05)

None

Hepatitis B

Kasapçopur et al. [16]

Turkey

2004

39 JIA (46%), 10.0 y (SD 3.3, range 4.0–16.0)

19 MTX, 17 steroids, 3 MTX + steroids

41 healthy (51%), 8.8 y (SD 2.6, range 5.0–14.0)

Single-centre, prospective cohort study (2B)

Engerix-B^®(GlaxoSmithKline)

10 μg (weight < 20 kg), 20 μg (weight > 20 kg)

3 (0; 1 m; 3 m or 6 m)

1 m

• Lower GMT in JIA (137.4 vs 258.9 mIU/mL, p = NA)

• Lower SPR in JIA (97 vs 100%, p = NA)

None

No difference in GMT for different treatments

No difference in GMT for different vaccine schedules (3rd dose at 3 or 6 m)

Human papillomavirus

Heijstek et al. [44]

Netherlands

2014

68 JIA (100%), 14.1 y (SD 1.6)

24 MTX, 9 anti-TNF-alpha, 5 leflunomide, 1 anti-IL-1, 1 mycophenolate mofetil¹

55 healthy (100%), 14.3 y (SD 1.2)

Single-centre, prospective cohort study (2B)

Cervarix^®(GlaxoSmithKline)

3 (0; 1 m; 6 m)

1 m

• No difference in GMT between JIA and controls

JIA: pain 52 (96%), induration 26 (48%), swelling 25 (46%) redness 20 (37%), bruising 14 (26%)

Controls: pain 44 (100%), redness 43 (98%), bruising 39 (89%), induration 21 (48%), swelling 18 (41%)

JIA: fatigue 30 (56%), myalgia 29 (54%), headache 22 (41%), arthralgia 11 (20%), rash 11 (20%), fever 6 (11%), syncope 1 (2%)

Controls: fatigue 22 (50%), headache 22 (50%), myalgia 19 (43%), arthralgia 6 (14%), rash 6 (14%), fever 3 (7%)

JIA: endoscopies 3 (4%), pre-planned surgeries 2 (3%), allergic reaction to anti-TNF-alpha 1 (1%), analyse of gait abnormalities 1 (1%), appendicitis 1 (1%), correction of cerebral arteriovenous malformation 1 (1%), epileptic insult (cerebral arteriovenous malformation) 1 (1%), perforated eardrum 1 (1%), pre-planned laser therapy uveitis 1 (1%), severe pharyngitis 1 (1%) transient lower back pain 1 (1%),

Controls: pre-planned surgery 1 (2%)

None

1 JIA (on MTX) did not reach seroprotection at 6 m

No difference in GMT between JIA on MTX and JIA on other treatments

6 m

• No difference in GMT between JIA and controls

• No difference in avidity of HPV16/18-specific IgGs between JIA and controls

Diphtheria, tetanus

Brunner et al. [41]

USA

2020

29 JIA (55%), 4.2 y (SD 0.9)

29 abatacept, 22 MTX, 3 steroids¹

Multicentre, cross-sectional study (2C)

Diphtheria and tetanus (NA)

• SPR for diphtheria in JIA 90%

• SPR for tetanus in JIA 100%

3 JIA did not reach seroprotection

No difference in SPR for different treatments

No difference in SPR for different vaccine types or schedule

Heijstek et al. [30]

Netherlands

2012

400 JIA (NA), 9.4 y (SD 4.5)

93 MTX, 28 steroids, 8 anti-TNF-alpha

2176 healthy (NA), 7.9 y (SD 5.5)

Single-centre, cross-sectional (2C)

Diphtheria and tetanus (Dutch National Institute of Public Health and the Environment/the Dutch Vaccine Institute)

6 (4 doses until age 1 y; 4 y; 9 y)

• Lower GMT for diphtheria in JIA (NA, p < 0.01)

• Lower GMT for tetanus in JIA (NA, p < 0.01)

• Lower SPR for diphtheria in JIA (91 vs 99%, p < 0.01)

• Lower SPR for tetanus in JIA (96 vs 99%, p < 0.01)

No difference in GMT between JIA on MTX and JIA on other treatments

No difference in GMT between JIA on steroids and JIA without steroids

• Lower GMT for diphtheria in JIA (NA, p < 0.01)

• Lower GMT for tetanus in JIA (NA, p < 0.01)

• Lower SPR for diphtheria in JIA (77 vs 99%, p < 0.01)

• Lower SPR for tetanus in JIA (94 vs 99%, p = 0.01)

Influenza

Camacho-Lovillo et al. [12]

Spain

2017

35 JIA (66%), median 10.6 y (IQR 8.8–12.7)

11 etanercept, 4 anakinra, 4 tocilizumab, 4 adalimumab (7 additional MTX), 7 MTX, 2 tocilizumab + MTX + steroids, 3 none

6 healthy (67%), median 11.6 y (IQR 9.8–14.6)

Single-centre, prospective cohort study (2B)

TIV (Sanofi Pasteur MSD)

• A/California/7/2009 (H1N1)pdm09

• A/Victoria/361/2011(H3N2)

• B/Massachusetts/2/2012

1 (> 9 y), 2 (< 9 y) (0; 1 m)

1–2 m

• No difference in GMT, SCR, SPR for any of the 3 strains between JIA and controls

Whole cohort⁴: local skin inflammation 6 (15%), haematoma 1 (2%)

JIA: general malaise and fever > 24 h 1 (3%)

Controls: general malaise and fever > 24 h 1 (17%)

None

JIA: 6 (17%)

No difference in GMT, SCR, SPR for any of the 3 strains for different biologicals or additional steroids

12 m

• No difference in GMT, SCR, SPR for any of the 3 strains between JIA and controls

No difference in GMT, SCR, SPR for any of the 3 strains for different biologicals or additional steroids

Aikawa et al. [22]

Brazil

2013

95 JIA (56%), 14.9 y (SD 3.2)

55 steroids, leflunomide, cyclosporine or SSZ, 47 MTX, 16 anti-TNF-alpha¹

91 healthy (52%), 14.6 y (SD 3.7)

Single-centre, prospective cohort study (2B)

NYMCx-179A (Butantan Institute/Sanofi Pasteur)

• A/California/7/2009 (H1N1)pdm09

15 μg

21 d

• Lower SCR in JIA (83 (95%CI 76–91) vs 96% (95%CI 91–100), p < 0.01)

• No difference in GMT and SPR between JIA and controls

JIA: local pain 20 (21%)

Controls: local pain 21 (23%)

JIA: myalgia 15 (16%), headache 14 (15%)

Controls: headache 18 (20%), myalgia 6 (7%)

None

Lower SCR in JIA with polyarticular disease⁵ compared to controls (80 (95%CI 68–92) vs 96% (95%CI 91–100, p < 0.01)

Lower SCR in JIA without anti-TNF-alpha compared to controls (81 (95%CI 72–90) vs 96% (95%CI 91–100), p < 0.05)

Lower SPR in JIA without anti-TNF-alpha compared to controls (86 (95%CI 78–94) vs 96% (95%CI 91–100), p < 0.05)

No difference in GMT for different treatments

Carvalho et al. [46]

Brazil

2013

44 JIA (NA), 11.0 y

31 leflunomide or MTX, 6 steroids, 5 anti-TNF-alpha, 1 cyclosporine

10 healthy (NA), mean NA (range 3.0–18.0)

Single-centre, prospective cohort study (2B)

TIV (Butantan Institute/Sanofi Pasteur SA)

• A/Solomon/3/2006(H1N1)

• A/Brisbane/10/2007(H3N2)

• B/Florida/4/2006

0.25 mL (1–3 y), 0.5 mL (> 3 y)

1 (> 9 y), 2 (< 9 y) (0; 1 m)

30–40 d

• Lower SCR for A/H1N1 strain in JIA (93 vs 100%, p = NA)

• Higher SCR for A/H3N2 strain in JIA (74 vs 38%, p = NA)

• Higher SCR for B strain in JIA (78 vs 75%, p = NA)

• Higher SPR for A/H3N2 strain in JIA (91 vs 80%, p = NA)

• Lower SPR for B strain in JIA (95 vs 100%, p = NA)

• No difference in SPR for A/H1N1 strain between JIA and controls

JIA: pain 6 (14%), redness and swelling 2 (7%)

Controls: pain 1 (10%), redness and swelling 1 (10%)

JIA: rhinorrhoea and cough 6 (14%)

Controls: None

None

Lower SCR for A/H1N1 strain in JIA on anti-TNF-alpha compared to other treatments (p = 0.03)

Lower SPR for A/H1N1 strain in JIA on anti-TNF-alpha compared to other treatments (p = NA)

No difference in SPR for A/H3N2 and B strains between JIA on anti-TNF-alpha and controls

Dell’Era et al. [31]

Italy

2012

30 JIA (73%), 8.4 y (SD 4.6)

30 MTX or SSZ

30 JIA (47%), 9.5 y (SD 5.7)

30 etanercept

30 healthy (50%), 9.1 y (SD 5.0)

Single-centre, prospective cohort study (2B)

TIV (Novartis)

• A/California/7/2009(H1N1)pdm09

• A/Perth/16/2009(H3N2)

• B/Brisbane/60/2008

15 μg

1 m

• Lower GMT for A/H1N1 strain in JIA on etanercept compared to JIA on MTX and controls (773.6 vs 1833.8 vs 1693.1, p < 0.05)

• Lower GMT for B strain in JIA on etanercept compared to JIA on MTX and controls (61.2 vs 187.7 vs 210.6, p < 0.05)

• Lower SCR for B strain in JIA on etanercept compared to JIA on MTX and controls (30 vs 83 vs 93%, p < 0.05)

• Lower SPR for B strain in JIA on etanercept compared to JIA on MTX and controls (30 vs 83 vs 93%, p < 0.05)

• No difference in GMT for A/H3N2 strain between JIA on etanercept, JIA on MTX or SSZ and controls

• No difference in SCR and SPR for A/H1N1 and A/H3N2 strains between JIA on etanercept, JIA on MTX or SSZ and controls

JIA on MTX or SSZ: pain 13 (43%), swelling 12 (40%), erythema 2 (7%)

JIA on etanercept: pain 11 (37%), swelling 11 (37%), erythema 3 (10%)

Controls: pain 12 (40%), swelling 11 (37%), erythema 3 (10%)

JIA on MTX or SSZ: rhinitis 9 (30%), changing eating habits 8 (27%), fever 7 (23%), malaise 6 (20%), sleepiness 6 (20%), diarrhoea 2 (7%), vomiting 2 (7%)

JIA on etanercept: malaise 8 (27%), rhinitis 8 (27%), changing eating habits 4 (13%), fever 4 (13%), sleepiness 4 (13%), vomiting 2 (7%), diarrhoea 1 (3%)

Controls: malaise 8 (27%), rhinitis 7 (23%), changing eating habits 5 (17%), fever 5 (17%), sleepiness 5 (17%), diarrhoea 2 (7%), vomiting 1 (3%)

JIA on etanercept: hospitalisation for fever and coxalgia 1 (3%)

Controls: none

JIA on MTX: 1 (3%)

3 m

• Lower GMT for A/H1N1 in JIA on etanercept compared to JIA on MTX and controls (463.4 vs 1067.7 vs 1324.5, p < 0.05)

• Lower GMT for B strain in JIA on etanercept compared to JIA on MTX and controls (33.3 vs 162.6 vs 193.3, p < 0.05)

• Lower SCR for B strain in JIA on etanercept compared to JIA on MTX and controls (10 vs 83 vs 90%, p < 0.05)

• Lower SPR for B strain in JIA on etanercept compared to JIA on MTX and controls (10 vs 83 vs 90%, p < 0.05)

• No difference in GMT for A/H3N2 strain between JIA on etanercept, JIA on MTX or SSZ and controls

• No difference in SCR and SPR for A/H1N1 and A/H3N2 strains between JIA on etanercept, JIA on MTX or SSZ and controls

Shinoki et al. [29]

Japan

2012

27 JIA (48%), 10.4 y (SD 5.6)

24 steroids + tocilizumab, 3 tocilizumab

17 healthy (47%), 10.6 y (SD 6.2)

Single-centre, prospective cohort study (2B)

TIV (NA)

• A/Solomon/3/2006(H1N1)

• A/Hiroshima/52/2005(H3N2)

• B/Malaysia/2506/2004

0.2 (1–6 y), 0.3 (6–13 y), 0.5 mL (> 13 y)

1 (> 13 y), 2 (< 13 y) (0; 7–28 d)

28–49 d

• No difference in GMT, SCR and SPR for any of the 3 strains between JIA and controls

JIA: local erythema and swelling 3 (11%), local induration 1 (4%)

Controls: none

JIA: influenza with fever and rhinorrhoea 1 (4%)

Controls: none

None

No difference in GMT for any of the 3 strains between JIA on tocilizumab since ≥ 2 y and JIA on < 0.2 mg/kg steroids

No difference in GMT for A/H3N2 and B strains between JIA on > 0.2 mg/kg steroids and JIA on < 0.2 mg/kg steroids

Toplak et al. [28]

Slovenia

2012

31 JIA (68%), 11.0 y (SD 4.5, range 3.0–18.0)

18 none, 8 MTX, 3 leflunomide, 2 SSZ, 7 steroids plus MTX, leflunomide or SSZ, 3 etanercept plus MTX, leflunomide or SSZ, 1 infliximab plus MTX, leflunomide or SSZ

14 children with cardiac diseases (29%), 11.9 y (SD 4.5, range 4.0–18.0)

Single-centre, prospective cohort study (2B)

Begrivac 2008/2009^®(Novartis)

• A/Brisbane/59/2007(H1N1)

• A/Brisbane/10/2007(H3N2)

• B/Florida/4/2006

15 μg

1, 2 (< 9 y + 1st dose) (0; 1 m)

1 m

• Lower GMT for A/H1N1 strain in JIA (174.9 vs 240.7, p = NA)

• Lower GMT for A/H3N2 strain in JIA (153.2 vs 158.7, p = NA)

• Higher GMT for B strain in JIA (100.2 vs 92.2, p = NA)

• Lower SCR for A/H1N1, A/H3N2, B strains in JIA (68 vs 79%, p = NA)

JIA: pain 10 (32%)

Controls: pain 3 (21%)

JIA: malaise and headache 1 (3%)

Controls: malaise 2 (14%)

None

JIA: 11 (35%)

1 m after vaccination 4

2 m after vaccination 1

6 m after vaccination 6

2 JIA and 1 control did not reach seroprotection for A/H1N1 strain

6 JIA and 3 controls did not reach seroprotection for A/H3N2 strain

5 JIA and 3 controls did not reach seroprotection for B strain

6 m

• Higher GMT for A/H1N1 strain in JIA (90.9 vs 72.7, p = NA)

• Lower GMT for A/H3N2 strain in JIA (86.3 vs 88.5, p = NA)

• Lower GMT for B strain in JIA (98.3 vs 113.5, p = NA)

• Lower SCR for A/H1N1, A/H3N2, B strains in JIA (77 vs 79%, p = NA)

Higher GMT for A/H1N1 (105.9 vs 90.9 vs 72.7, p = NA), A/H3N2 (95.4 vs 86.3 vs 88.5, p = NA) and B strains (113.8 vs 98.3 vs 113.5, p = NA) in JIA on MTX, leflunomide or SSZ compared to JIA on other treatments and controls

Meningococcus C

Stoof et al. [20]

Netherlands

2014

127 JIA (62%), 8.9 y (SD 3.7)

108 MTX, 44 etanercept, 14 steroids, 6 infliximab, 9 anakinra, 1 anti-IL-6

1527 healthy (54%), 9.1 y (SD 5.1)

Single-centre, retrospective cohort study (2B)

NeisVac-C^®(Baxter Healthcare)

19 μg (N. meningitidis serogroup C polysaccharide strain C11), 10–20 μg (tetanus toxoid)

50 m

• No difference in GMT between JIA and controls

No difference in GMT decrease in JIA starting MTX treatment during the study

Zonneveld-Huijssoon et al. [26]

Netherlands

2007

234 JIA (65%), 11.1 y (SD 4.2, range 1.5–18.9)

Group I: 47 none

Group II: 41 NSAID

Group III: 36 MTX, 7 SSZ

Group IV: 15 MTX, 6 etanercept, 2 infliximab, 2 MTX + SSZ, 1 cyclosporine

Multicentre, prospective cohort study (2B)

NeisVac-C^®(NA)

20 μg/mL (N. meningitides Z2491 serogroup C polsysaccharide), 20–40 μg/mL (tetanus toxoid)

< 3 m

• Lower GMT in group III and IV compared to group I and II (17.5 vs 16.3 vs 41.0 vs 46.9 μg/mL, p ≤ 0.01)

• No difference in GMT between group III and group IV

None

Low GMT (< 2 µg/mL) in 4 JIA (2 on etanercept + MTX, 1 on MTX, 1 on SSZ)

Pneumococcus

Aikawa et al. [19]

Brazil

2015

17 JIA (47%), median 11.6 y

17 etanercept, 16 MTX, 6 steroids, 4 cyclosporine, 4 leflunomide¹

10 JIA (40%), median 9.2 y

10 MTX, 1 cyclosporine¹

Single-centre, prospective cohort study (2B)

Pneumovax^®(Sanofi Pasteur)

2 m

• No difference in GMT, SCR, SPR for serotypes 4, 6B, 9 V, 14, 18C, 19F, 23F between JIA on etanercept and controls

JIA on etanercept: none

Controls: swelling and redness 1 (10%)

JIA on etanercept: upper respiratory tract infection requiring antibiotics 11 (65%)

Controls: upper respiratory tract infection requiring antibiotics 3 (30%)

JIA on etanercept: invasive pneumococcal disease with a bacterial pneumonia requiring hospitalization 1 (6%)

Controls: none

None

12 m

• No difference in GMT, SCR, SPR for serotypes 4, 6B, 9 V, 14, 18C, 19F, 23F between JIA on etanercept and controls

Farmaki et al. [38]

Greece

2010

31 JIA (68%), 12.9 y (SD 4.6)

26 MTX, 21 etanercept, 10 adalimumab, 8 steroids, 5 cyclosporine¹

32 JIA (78%), 11.6 y (SD 3.3)

26 MTX, 8 steroids, 7 cyclosporine¹

Single-centre, prospective cohort study (2B)

Prevenar^®(NA)

2 (0; 42–56 d)

Mean 42 d (SD 3.3) after 1st dose

• Lower GMT for serotypes 4 (1.8 vs 5.0 μg/mL, p < 0.01), 14 (5.5 vs 10.3 μg/mL, p = 0.01) and 23F (4.5 vs 11.2 μg/mL, p = 0.02) in JIA on etanercept or adalimumab

• No difference in SPR for serotypes 4, 6 V, 9 V, 14, 18C, 19F, 23F

JIA on etanercept or adalimumab 6 (19%): pain, redness, swelling

Controls 5 (16%): pain, redness, swelling

None

JIA on etanercept or adalimumab: 1 (3%)

No difference in GMT and SPR for JIA on adalimumab compared to JIA on etanercept

Mumps, measles, rubella

Heijstek et al. [45]

Netherlands

2013

Group 1: 63 JIA (73%), 6.3 y (95%CI 5.9–6.7)

29 MTX, 5 etanercept, 3 anti-IL-1, 2 steroids, 1 adalimumab, 1 leflunomide¹

Group 2: 68 JIA (60%), 6.5 y (95%CI 6.2–6.9)

31 MTX, 4 etanercept, 1 anti-IL-1, 1 leflunomide, 1 steroids¹

Multicentre, non-blinded, controlled, randomised trial (1B)

MMR-NV1^®(Netherlands vaccine Institute) or M-M-RVAXPRO^®(Sanofi Pasteur)

1 MMR booster in group 1

12 m

• Higher GMT for measles in JIA with MMR booster (1.6 vs 0.8 IU/mL, p = 0.03)

• Higher GMT for mumps in JIA with MMR booster (168.0 vs 104.0 RU/mL, p = 0.03)

• Higher GMT for rubella in JIA with MMR booster (69.0 vs 45.0 IU/mL, p = 0.01)

• Higher SPR for measles in JIA with MMR booster (100 vs 92% (95%CI 84–99), p = ns)

• Higher SPR for mumps in JIA with MMR booster (97 (95%CI 95–100) vs 81% (95%CI 72–93), p = ns)

• Higher SPR for rubella in JIA with MMR booster (100 vs 94% (95%CI 86–100), p = ns)

Group 1: abdominal pain and/or obstipation 4 (6%), bone fracture due to trauma 4 (6%), upper respiratory tract infection 4 (6%), arthralgia 3 (5%), contusion due to trauma 3 (5%), gastroenteritis 3 (5%), otitis 3 (5%), rash 3 (5%), eczema 2 (3%), fever 2 (3%), molluscum contagiosum 2 (3%), bronchopneumonia 1 (2%), CRP elevation 1 (2%), fungal infection 1 (2%), headache 1 (2%), varicella infection 1 (2%), worsening of pre-existent anxiety attacks 1 (2%)

Group 2: contusion due to trauma 4 (6%), gastroenteritis 4 (6%), abdominal pain and/or obstipation 3 (4%), rash 3 (4%), upper respiratory tract infection 3 (4%), viral infection 3 (4%), eczema 2 (3%), myalgia 2 (3%), A/H1N1 infection 1 (1%), fever 1 (1%), headache 1 (1%), impetigo 1 (1%), molluscum contagiosum 1 (1%), vaginal discharge 1 (1%), watery discharge from the eyes 1 (1%)

Group 1: hospital admissions 3 (5%), surgery 2 (3%)

Group 2: surgery 6 (9%), hospital admission 5 (7%)

None

No difference in GMT at 3 and 12 m in JIA on MTX and JIA on other treatments

5 controls were not seroprotected for measles

2 JIA (1 on MTX, 1 on MTX + etanercept) and 12 controls

did not reach seroprotection for mumps

4 controls did not reach seroprotection for rubella

Heijstek et al. [30]

Netherlands

2012

400 JIA (NA), 9.4 y (SD 4.5)

93 MTX, 28 steroids, 8 anti-TNF-alpha (NA)¹

2176 healthy (NA), 7.9 y (SD 5.5)

Single-centre, cross-sectional study (2C)

MMR (Dutch National Institute of Public Health and the Environment/the Dutch Vaccine Institute)

2 (age 14 m and 9 y)

• Higher GMT for measles in JIA (NA, p < 0.01)

• Lower GMT for mumps in JIA (NA, p < 0.01)

• Lower GMT for rubella in JIA (NA, p < 0.01)

• Higher SPR for measles in JIA (94 vs 87%, p = 0.01)

• No difference in SPR for mumps between JIA and controls

• No difference in SPR for rubella between JIA and controls

Higher GMT for measles (p = 0.02) in JIA with high disease activity

No difference in GMT between JIA on MTX and JIA on other treatments

No difference in GMT between JIA on steroids and JIA without steroids

Monovalent measles (NA) vaccine plus MMR (NA) or rubella (Dutch National Institute of Public Health and the Environment)

2 (age 14 m and 4 y or 11 y)

• Higher GMT for measles in JIA (NA, p < 0.01)

• Lower GMT for mumps in JIA (NA, p < 0.01)

• Lower GMT for rubella in JIA (NA, p < 0.01)

• Lower SPR for mumps in JIA (81 vs 95%, p < 0.01)

• Lower SPR for rubella in JIA (81 vs 99%, p < 0.01)

• No difference in SPR for measles between JIA and controls

Borte et al. [14]

Germany

2009

15 JIA (NA)

Group I: 5 MTX start > 4 y after MMR, 15.8 y (range 14.2–17.9)

Group II: 5 MTX ≥ 6 m before MMR, 6.7 y (range 6.6–6.7)

Group III: 5 etanercept + MTX ≥ 6 m before MMR, 6.3 y (range 6.0–6.7)

Group IV: 22 healthy (NA), 11.2 y (range 1.0–20.0)

Single-centre, prospective nested case–control study (3B)

MMR (NA)

2 (age 13–24 m and 6 y)

Group I: 6 m after MTX start

• Lower GMT for measles in JIA (group I) compared to healthy children (group V) (194.3 (IQR 0.0–410.0) vs. 1231.7 IU/mL (IQR 461.0–1730.0), p < 0.05)

• No difference in GMT for mumps between JIA (group I) and controls

• No difference in GMT for rubella between JIA (group I) and controls

None

Group II, III, IV: 6 m after vaccination

• No difference in GMT for measles, mumps and rubella between JIA (group II, III) and controls (group IV)

Systemic lupus erythematosus (SLE)

Hepatitis B

Aytac et al. [34]

Turkey

2011

20 SLE (80%), 13.2 y (SD 2.6, range 9.1–19.8)

17 steroids, 11 azathioprine, 3 mycophenolate mofetil, 3 none, 2 hydroxychloroquine¹

24 healthy (50%), 8.8 y (SD 2.7, range 5.0–14.0)

Single-centre, prospective cohort study (2B)

Engerix-B^®(GlaxoSmithKline)

10 μg (weight < 20 kg), 20 μg (weight > 20 kg)

3 (0; 1; 6 m)

1 m

• Lower GMT in SLE (310.4 (range 0.0–500.0) vs 618.5 IU/mL (range 70.0–900.0), p = NA)

• No difference in SPR between SLE and controls

None

SLE: 3 (15%)

Tetanus

Miyamoto et al. [36]

Brazil

2011

20 inactive SLE (85%), 14.0 (SD 2.0; range 10.0–17.0)

17 chloroquine, 14 steroids, 8 azathioprine, 2 cyclosporine, 2 MTX, 1 mycophenolate mofetil¹

10 active SLE (90%), 12.0 (SD 2.0; range 8.0–14.0)

14 steroids, 8 chloroquine, 6 azathioprine, 2 cyclophosphamide¹

14 healthy (71%), 14.0 y (SD 3.0, range: 8.0–18.0)

Single-centre, retrospective case–control (3B)

DTP (NA)

5 (age 2, 4, 6, 15 m and 4–6 y)

• Lower GMT in inactive SLE (0.14 vs 0.68 IU/mL, p < 0.05)

• No difference in GMT between active SLE and controls

Kashef et al. [15]

Iran

2008

40 SLE (80%), 14.1 y (range 7.0–21.0)

13 azathioprine + steroids, 10 cyclophosphamide + steroids, 8 mycophenolate mofetil + steroids, 5 azathioprine + cyclophosphamide + steroids

60 healthy (69%), 14.4 y (range NA)

Multicentre, retrospective case–control study (3B)

Tetanus (NA)

5 (until age 6 y)

• No difference in GMT between SLE and controls

SLE: disseminated infections requiring hospital admission 4 (10%)

Controls: none

Influenza

Campos et al. [21]

Brazil

2013

118 SLE (77%), 16.0 y (SD 3.5)

92 antimalarials, 83 steroids, 44 azathioprine, 15 mycophenolate mofetil, 14 MTX, 3 cyclophosphamide, 2 cyclosporine¹

102 healthy (50%), 15.9 y (SD 4.5)

Single-centre, prospective cohort study (2B)

NYMCX-179A (Butantan Institute/Sanofi Pasteur)

• A/California/7/2009(H1N1) pdm09

15 μg

21 d

• Lower GMT in SLE (90.8 (95%CI 67.8–121.7) vs 237.3 NA (95%CI 188.8–298.3), p < 0.01)

• Lower SCR in SLE (64 (95%CI 54–72) vs 91% (95%CI 84–96), p < 0.01)

• Lower SPR in SLE (74 (95%CI 65–81) vs 95% (95%CI 89–98), p < 0.01)

SLE: itching 20 (17%), redness 13 (11%)

Controls: redness 2 (2%)

SLE: arthralgia 20 (17%), rhinorrhoea 15 (13%)

Controls: rhinorrhoea 4 (4%), arthralgia 1 (1%)

None

Children with SLE on higher steroid doses (18.0 mg/d (SD 21.4)) did more frequently not seroconvert than children with SLE on lower doses (10.5 mg/d (SD 12.5))

Lower frequency of renal involvement in SLE 4 m after-vaccination compared to baseline (28 vs 51%, p < 0.01)

Higher frequency of mucocutaneous lesions in SLE 4 m after-vaccination compared to baseline (17 vs 6%, p = 0.02)

Measles

Miyamoto et al. [36]

Brazil

2011

20 inactive SLE (85%), 14.0 (SD 2.0; range 10.0–17.0)

17 chloroquine, 14 steroids, 8 azathioprine, 2 cyclosporine, 2 MTX, 1 mycophenolate mofetil¹

10 active SLE (90%), 12.0 (SD 2.0; range 8.0–14.0)

14 steroids, 8 chloroquine, 6 azathioprine, 2 cyclophosphamide¹

14 healthy (71%), 14.0 y (SD 3.0, range: 8.0–18.0)

Single-centre, retrospective case–control (3B)

Measles (NA)

2 (after age 2 y)

• No difference in GMT between active SLE, inactive SLE and controls

Lower IgM titres in inactive SLE (1.2 vs 1.7 g/l, p = 0.03)

No difference in IgA and IgG titres between active and inactive SLE and controls

Varicella

Barbosa et al. [47]

Brazil

2012

28 SLE (75%), 15.3 y (SD 2.5, range 9.9–18.8)

27 chloroquine, 18 steroids, 9 azathioprine, 2 MTX¹

28 healthy (75%), 15.0 y (SD 2.5, range 10.1–18.7)

Multicentre, blinded, controlled, randomised trial (1B)

Oka strain (Biken)

> 10³ PFU

1 m

• No difference in GMT between SLE and controls

SLE 2 (7%): NA

Controls 6 (21%): NA

SLE: headache 10 (36%), fever 3 (11%), rash 1 (4%)

Controls: headache 6 (21%), fever 4 (14%), vomiting 1 (4%), rash 1 (4%)

None

6 m

• No difference in GMT between SLE and controls

12 m

• No difference in GMT between SLE and controls

Juvenile autoimmune rheumatic disease (JARD)

Hepatitis A and B

Belderok et al. [17]

Netherlands

2013

78 JARD (71 JIA, 2 SLE, 2 uveitis, 1 autoinflammatory syndrome, 1 JDM, 1 panuveitis) (64%), median 12.0 y (IQR 9.0–14.0)

42 MTX, 24 MTX + anti-TNF-alpha (adalimumab, etanercept or infliximab), 2 MTX + anti-TNF-alpha + steroids, 4 anti-TNF-alpha, 1 anakinra, 1 anti-TNF-alpha + cyclosporine, 1 azathioprine, 1 cyclosporine, 1 MTX + anakinra, 1 MTX + steroids, 1 mycophenolate mofetil, 1 mycophenolate mofetil + steroids

Multicentre, prospective cohort study (2B)

Ambirix^®(GlaxoSmithKline)

720 ELISA units (HAV), 20 μg (hepatitis B surface antigen)

2 (0; 6–7 m)

35 d

• GMT for HAV in JARD (288.0 mIU/mL)

• GMT for HBV in JARD (321.0 mIU/mL)

• Positive SCR for HAV in JARD (100% (95%CI 96–100))

• Positive SCR for HBV in JARD (93% (95%CI 86–98))

No difference in GMT for different treatments

Human papillomavirus

Heijstek et al. [48]

Netherlands

2013

12 JARD (6 JDM, 6 SLE) (100%)

age JDM vs SLE 15.3 (SD 2.3) vs 15.0 (SD 1.5) 6 steroids, 5 none, 2 hydroxychloroquine, 2 MTX, 1 azathioprine, 1 mycophenolate mofetil¹

49 healthy (100%), 14.3 y (SD 1.2)

Single-centre, prospective cohort study (2B)

Cervarix^®(GlaxoSmithKline)

3 (0; 1; 6 m)

1 m

• Lower GMT for HPV16 (NA, p < 0.01) and HPV18 (NA, p = 0.04) in JARD

JDM 1 (17%)

1 JDM did not seroconvert (without immunosuppressive drugs)

6 m

• No difference in GMT between JARD and controls

Tetanus

Ingelman-Sundberg et al. [40]

Sweden

2016

50 JARD (46 JIA, 1 erythema nodosum with arthritis, 1 JDM, 1 mixed connective tissue disease, 1 polyarteritis nodosa) (64%)

median age: JARD on MTX 12.2 y (range 6.0–16.0); anti-TNF-alpha + MTX 13.1 y (range 2.9–18.3); no treatment 13.8 y (range 4.3–16.0)

15 etanercept, 10 MTX, 8 adalimumab + MTX, 8 none, 7 infliximab + MTX, 2 golimumab + MTX (some on additional steroids)

31 healthy (32%), median 11.5 y (range 2.4–17.7)

Single-centre, cross-sectional study (2C)

DTP (NA)

≥ 3 doses⁶

• Lower GMT for tetanus following booster in JARD on anti-TNF-alpha + MTX or MTX compared to JARD without treatment and healthy controls (NA, p = 0.02)

• No difference in GMT for tetanus following booster for different treatments in JARD

Lower transition B cell proportions in JARD (NA, p < 0.01)

Lower transition B cell proportions in JARD on anti-TNF-alpha compared to JARD without anti-TNF-alpha and controls (NA, p < 0.01)

Influenza

Aikawa et al. [18]

Brazil

2013

38 JARD (25 JIA, 5 JDM, 3 JScle, 3 SLE, 2 vasculitis) (76%), median 7.0 y (range 2.6–9.0)

23 MTX, 12 steroids, 7 anti-TNF-alpha, 6 cyclosporine, 5 none, 1 azathioprine, 1 leflunomide¹

11 healthy (64%), median 7.8 y (range 3.2–8.9)

Single-centre, prospective cohort study (2B)

NA (Butantan Institute/Sanofi Pasteur)

• A/California/7/2009(H1N1) pdm09

15 μg

2 (0; 21 d)

• No difference in GMT, SCR and SPR between JARD and controls

JARD: pain 4 (11%)

Controls: pain 2 (18%)

JARD: headache 6 (16%), cough 4 (11%), fever 4 (11%), malaise 3 (8%), myalgia 2 (5%), rhinorrhoea 2 (5%), arthralgia 1 (3%)

Controls: fever 1 (9%)

None

7 JARD (6 JIA, 1 SLE) did not seroconvert

Aikawa et al. [32]

Brazil

2012

237 JARD (99 SLE, 93 JIA, 18 JDM, 11 JScle, 16 primary vasculitis) (66%), 14.8 y (SD 3.0)

90 steroids, 74 MTX, 43 azathioprine, 23 cyclosporine, 13 mycophenolate mofetil, 6 leflunomide, 3 cyclophosphamide¹

91 healthy (52%), 14.6 y (SD 3.7)

Single-centre, prospective cohort study (2B)

NYMCx-179A (Butantan Institute/Sanofi Pasteur)

• A/California/7/2009(H1N1) pdm0915 μg

21 d

• Lower GMT in JARD (147.2 (95%CI 119.7–181.1) vs 250.8 IU/mL (95%CI 196.3–320.3), p = 0.01)

• Lower SCR in JARD (74 (95%CI 69–80%) vs 96% (95%CI 91–100%), p < 0.01)

• Lower SPR in JARD (81 (95%CI 77–86%) vs 96% (95%CI 91–100%), p < 0.01)

JARD: pain 43 (18%), itching 19 (8%), redness 9 (4%), swelling 3 (1%)

Controls: pain 21 (23%), redness 21 (23%), swelling 2 (1%)

JARD: headache 41 (17%), arthralgia 31 (13%), myalgia 27 (11%), rhinorrhoea 19 (8%), cough 16 (7%), fever 13 (6%), nasal congestion 13 (6%), sore throat 9 (4%), diarrhoea 8 (3%)

Controls: headache 18 (20%), myalgia 6 (7%), cough 5 (6%), sorethroat 5 (6%), fever 3 (3%), nasal congestion 3 (3%), rhinorrhoea 3 (3%), arthralgia 2 (2%), diarrhoea 2 (2%)

None

Lower GMT in SLE compared to controls (91.1 (95%CI 66.0–125.8) vs 250.8 IU/mL (95%CI 196.3–320.3), p > 0.05)

Lower GMT in JARD on azathioprine (NA, p = 0.02) and mycophenolate mofetil (NA, p = 0.01) compared to JARD on other treatments

Lower SCR in SLE (64% (95%CI 54–73), p < 0.01), JIA (83% (95%CI 75–91), p = 0.01), JDM (78% (95%CI 59–97), p = 0.03) and primary vasculitis (75 (95%CI 54–96), p = 0.02) compared to controls (96% (95%CI 91–100%)

Lower SCR in JARD on steroids compared to JARD without steroids (60 vs 83%, p < 0.01)

Lower SCR in JARD on immunosuppressive drugs and steroids compared to JARD without immunosuppressive drugs and steroids (65 vs 78%, p = 0.04)

Lower SPR in SLE compared to controls (73.7 (95%CI 65.0–82.4 vs 96% (95%CI 91–100%), p < 0.01)

Woerner et al. [33]

Switzerland

2011

36 JARD (25 JIA, 3 uveitis, 2 inflammatory bowel disease, 2 chronic recurrent multifocal osteomyelitis, 1 JDM, 1 vasculitis, 1 SLE, 1 mixed connective tissue disease) (64%), median 13.8 y (range 2.3–16.0)

18 MTX, 10 anti-TNF-alpha, 8 anti-TNF-alpha + MTX

16 children with diabetes mellitus or cystic fibrosis (50%), median 11.9 y (7.8–15.1)

Single-centre, prospective cohort study (2B)

Inflexal V^®(Crucell Switzerland)

2007/2008

• A/Solomon/3/2006(H1N1)

• A/Wisconsin/67/2005(H3N2)

• B/Malaysia/2506/2004

2008/2009

• A/Brisbane/59/2007(H1N1)

• A/Brisbane/10/2007(H3N2)

• B/Florida/4/2006

7.5 μg (> 3 y) or 15 μg (< 3 y + 1st dose)

1, 2 (< 3 y + 1st dose) (0; 1 m)

1–2 m

• No difference in GMT, SCR and SPR for any of the 3 strains between JARD and controls

JARD: pain or tenderness 5 (14%)

Controls: pain or tenderness 2 (13%)

JARD: fever, headache or myalgia 4 (12%)

Controls: fever, headache or myalgia 1 (7%)

None

No difference GMT, SCR and SPR for different treatments

Ogimi et al. [37]

Japan

2011

49 JARD (23 JIA, 12 SLE, 6 JDM, 2 mixed connective tissue disease, 2 Kawasaki, 2 Takayasu arteritis, 1 Crohn’s disease, 1 Wegener granulomatosis) (71%), 12.1 y (SD 4.8)

14 steroids, 7 MTX + steroids, 7 mycophenolate mofetil + steroids, 6 cyclosporine + MTX + steroids, 2 azathioprine + steroids, 2 cyclosporine, 2 mizoribine + steroids, 1 azathioprine + cyclosporine + MTX, 1 azathioprine + cyclosporine + steroids, 1 azathioprine + mizoribine + steroids, 1 azathioprine + MTX + steroids, 1 cyclosporine + mizoribine + steroids, 1 cyclosporine + mycophenolate mofetil + steroids, 1 infliximab + MTX + steroids, 1 MTX, 1 MTX + tacrolimus + steroids

36 healthy (36%), 8.6 y (SD 14.3)

Single-centre, prospective cohort study (2B)

TIV (Kaketsuken, BIKEN)

• A/H1N1 (NA)

• A/H3N2 (NA)

• B (NA)

0.1 (< 1 y), 0.2 (1–5 y), 0.3 (6–12 y), 0.5 mL (> 13 y)

2 (7–28 d)

14–28 d

• Higher GMT for B strain in JARD⁷ (60.3 vs 23.8, p < 0.01)

• No difference in GMT for A/H1N1 and A/H3N2 strain between JARD and controls

• No difference in SCR for any of the 3 strains between JARD and controls

JARD: pain and swelling 1 (2%)

Controls: pain and/or swelling 3 (8%)

None

JARD 2 (4%)

Kanakoudi–Tsakalidou et al. [27]

Greece

2001

70 JARD (49 JIA, 11 SLE, 3 JDM, 3 systemic vasculitis, 2 connective tissue disease, 1 Behçet’s disease, 1 idiopathic recurrent pericarditis) (73%), 11.6 y (SD 4.5)

16 MTX + steroids, 16 steroids, 11 cyclosporine + steroids, 8 cyclosporine + MTX + steroids, 6 azathioprine + steroids, 5 MTX, 4 cyclosporine, 4 cyclosporine + MTX

Single-centre, prospective case series (4)

Fluarix^®SB (NA)

• A/Beijing/262/95(H1N1)

• A/Sydney/5/97(H3N2)

• B/Beijing/184/93

1, 2 (4–8 y and low pre-vaccination GMT) (0; 1 m)

1 m

• GMT for A/H1N1 (492.0), A/H3N2 (1449.0) and B strains (112.0) in JARD

• SPR for A/H1N1 (97%), A/H3N2 (100%) and B strains (80%) in JARD

• No difference in GMT and SPR for any of the 3 strains between JIA and SLE

• No difference in GMT and SPR for any of the 3 strains for different treatments

JARD: 3 pain (4%), redness 1 (1%)

JARD: fever and convulsion 1 (1%)⁸, sore throat and cough 1 (1%)

None

Higher increase in seroprotection for A/H1N1 compared to B strain after the 2nd vaccination in JARD with non-protective titre prior to 2nd vaccination (68% vs 5% (p < 0.01))

15 JARD (13 JIA, 1 SLE, 1 systemic vasculitis) did not reach seroprotection

Measles, rubella

Ingelman-Sundberg et al. [40]

Sweden

2016

50 JARD (46 JIA, 1 erythema nodosum with arthritis, 1 JDM, 1 mixed connective tissue disease, 1 polyarteritis nodosa) (64%)

median age JARD on MTX vs anti-TNF-alpha + MTX vs none 12.2 y (range 6.0–16.0) vs 13.1 y (range 2.9–18.3) vs 13.8 y (range 4.3–16.0)

15 etanercept, 10 MTX, 8 adalimumab + MTX, 8 none, 7 infliximab + MTX, 2 golimumab + MTX (some on additional steroids)

31 healthy (32%), median 11.5 y (range 2.4–17.7)

Single-centre, cross-sectional study (2C)

MMR (NA)

≥ 1 doses⁶ (1st dose before age 18 m)

• No difference in GMT for measles and rubella between JARD with/without booster and healthy with/without booster

Lower transition B cell proportions in JARD (NA, p < 0.01)

Lower transition B cell proportions in JARD on anti-TNF-alpha compared to JARD without anti-TNF-alpha and controls (NA, p < 0.01)

Low avidity range for rubella in 1 JARD (NA, p = 0.02)⁹

Varicella

Speth et al. [24]

Germany

2018

14 JARD (11 JIA, 2 JDM, 1 microscopic polyangiitis) on HIIS (71%), median 9.7 y (range 2.7–17.8)

2 etanercept, 2 MTX, 1 abatacept + leflunomide, 1 adalimumab + MTX, 1 anakinra + leflunomide + steroids, 1 anakinra + MTX + steroids, 1 etanercept + leflunomide + steroids, 1 etanercept + steroids, 1 leflunomide, 1 leflunomide + tocilizumab, 1 MTX + tocilizumab, 1 mycophenolate mofetil

9 JIA on LIIS (89%), median 8.3 y (range 1.8–17.8)

9 MTX

Single-centre, prospective cohort study (2B)

Varilrix^®(GlaxoSmithKline)

10^3.3 PFU

2 (42 d (LIIS), 3 m (HIIS))

1–3 m

• No difference in GMT between JARD on HIIS and JARD on LIIS

JARD on HIIS 1 (7%): NA

JARD on LIIS 1 (11%): NA

JARD on HIIS: arthralgia 1 (7%), elevated temperature 1 (7%), headache 1 (7%), vomiting 1 (7%)

JARD on LIIS: arthralgia 3 (33%)

None

Low IgG levels (< 200 mIU/mL) in 2 JARD (1 on mycophenolate mofetil, 1 on leflunomide and abatacept) after 2nd vaccination

Groot et al. [25]

Netherlands

2017

49 JARD (39 JIA, 5 JDM, 5 JScle) (53%)

1 vs 2 doses 5.0 y (range 2.0–15.0) vs 3.5 y (range 2.0–17.0)

25 MTX, 16 MTX + steroids, 2 cyclosporine + MTX, 2 leflunomide + MTX, 1 abatacept + MTX, 1 adalimumab + MTX, 1 azathioprine + MTX, 1 etanercept + MTX, 1 MTX + penicillamine

18 healthy (50%) median 8.5 y (range 3.0–18.0)

Single-centre, prospective cohort study (2B)

Oka strain (Biken)

> 10³ PFU

if 2nd dose: Varilrix® (NA)

10^3.3 PFU

28–42 d after 1st dose

• No difference in GMT between JIA, JDM or JScle and controls

None

JIA: elevated temperature (< 38 °C) and vesicular rash 2 (3%)

JScle: elevated temperature (< 38 °C) and vesicular rash 1 (20%)

Controls: fever 1 (6%)

None

JIA: 3 (8%)

1 JARD (on abatacept) did not reach seroprotection after 2nd dose

Higher GMT in JARD with 2 doses compared to JARD and controls with 1 dose (NA, p < 0.01)

No difference in GMT for different treatments

12 m after 1st dose

• No difference in GMT between JIA, JDM, JScle and controls

Pileggi et al. [39]

2010

Brazil

25 JARD (17 JIA, 4 JDM, 2 JScle, 1 vasculitis) (52%), median 7.2 y (range 2.0–19.0)

12 MTX, 8 MTX + steroids, 3 cyclosporine + MTX + steroids, 1 leflunomide + MTX + steroids, 1 MTX + penicillamine + steroids

18 healthy (NA), median 9.3 y (range 3.0–18.0)

Single-centre, prospective cohort study (2B)

Oka strain (NA)

0.5 mL

28–42 d

• No difference in GMT and SPR between JARD and controls

None

JARD: fever 1 (4%), rash 3 (12%)

Controls: fever 1 (6%)

None

2 JARD who did not reach seroprotection developed varicella

12 m

• SPR in JARD (80%)

95%CI 95% confidence interval, ANA antinuclear antibody, anti-IL anti-interleukin, anti-TNF-alpha anti-tumour necrosis factor alpha, d days, DT diphtheriae-tetanus vaccine, DTP diphtheria-tetanus-pertussis vaccine, ERA enthesitis-related arthritis, GMT geometric mean titre, HAV hepatitis A virus, HBV hepatitis B virus, HIIS high-intensity immunosuppression, HPV human papillomavirus, IQR interquartile range, IU international unit, IVIG intravenous immunoglobulins, JARD juvenile autoimmune rheumatic disease, JDM juvenile dermatomyositis, JIA juvenile idiopathic arthritis, JScle juvenile scleroderma, LIIS low-intensity immunosuppression, m month, MMR mumps-measles-rubella vaccine, MTX methotrexate, NA not available, NSAID non-steroidal anti-inflammatory drug, PFU plaque forming units, RU relative unit, SCR seroconversion rate, SD standard deviation, SLE systemic lupus erythematosus, SPR seroprotection rate, SSZ sulfasalazine, TIV trivalent influenza vaccine, y year

¹Some children were receiving more than one drug

²Time after initiation of adalimumab (mean duration between last dose and sampling in children with ERA 7.2 (SD 3.2) vs healthy children 8.4 years (SD 2.0))

³Summary of all reactions occurring after 1st, 2nd, and 3rd vaccination in 128 JDM and 112 controls

⁴Numbers for children and controls not specified separately

⁵Higher use of immunosuppressive drugs in polyarticular onset JIA compared with oligoarticular JIA (80 vs 42% (p < 0.01))

⁶Children divided into a vaccinated group without booster (3 DTP, 1 MMR dose) and a group with booster vaccination (> 3 DTP, > 1 MMR)

⁷ Elevated GMT before vaccination in JARD compared to controls (19.7 vs 10.8 (p < 0.01))

⁸Child with epilepsy

⁹‘High avidity’ defined as > 60%, ‘borderline avidity’ as 40–59%, ‘low avidity’ as < 40%