Table 2.
Critical appraisal of available evidence on immunogenicity and safety of vaccines in pedRD
| Vaccine | Patients | Medication | LoE | Immunogenicity | Safety |
|---|---|---|---|---|---|
| Live-attenuated | |||||
| Bacillus Calmette-Guérin | |||||
| Hsu et al. [44] | 281 KD | Unknown | 3 | – | Local inflammation at BCG vaccination site in up to 50 % of KD patients. |
| Kuniyuki et al. [45] | 1 KD | Unknown | 4 | – | Case report of local inflammation at BCG vaccination site. |
| Antony et al. [46] | 2 KD | Unknown | 4 | – | Case report of local inflammation at BCG vaccination site. |
| Weinstein [47] | 1 KD | Unknown | 4 | – | Case report of local inflammation at BCG vaccination site. |
| Chalmers et al. [48] | 1 KD | Unknown | 4 | – | Case report of local inflammation at BCG vaccination site. |
| Kiray et al. [27] | 115 JIA 45 HC |
55 GC 73 MTX 17 sulphasalazine |
2B | PPD reactivity several years after 1–2 BCG vaccinations: induration size smaller in JIA patients, 39 % JIA versus 84 % HC reacted to PPD. No influence of IS drugs. | – |
| Uehara et al. [49] | 15,524 KD | Unknown | 3 | – | Local inflammation at BCG vaccination site in 50 % of KD patients. |
| Measles, mumps, rubella | |||||
| Drachtman et al. [50] | 1 ITP | None | 4 | – | Case report of a flare of ITP 7 weeks after MMR booster. |
| Heijstek et al. [27] | 207 JIA | 49 MTX | 2B | – | No increase in disease activity. |
| Borte et al. [34] | 15 JIA 22 HC |
5 MTX 4 years post MMR 5 MTX 5 MTX + anti-TNFα |
2B | No interference of MTX or anti-TNFα with cellular or humoral immunity. | No increase in disease activity or medication use after MMR booster. No influence of MTX or anti-TNFα. |
| Korematsu et al. [51] | 1 JIA | NSAIDS | 4 | – | Case report of a flare of systemic JIA 5 days after rubella vaccination. |
| Miyamoto et al. [20] | 30 JSLE 14 HC |
25 HCQ 19 oral GC 14 AZA 9 IV GC 2 CFMpulse 2 CY 2 MTX 1 MMF |
2B | At 7–16 years after vaccination, protective antibody levels against measles were similar in patients and controls. | – |
| Heijstek et al. [18] | 400 JIA 2176 HC |
246 NSAID 93 MTX 28 oral GC (median dose 10 mg/day) 24 DMARD 8 anti-TNFα |
2C | Protective antibody levels against mumps and rubella in patients were lower after past vaccination (time since vaccination up to 10 years; adjusted OR for seroprotection between 0.1 and 0.4). Protective antibody levels against measles did not significantly differ from controls. |
- |
| Heijstek et al. [14••] | 68 JIA patients (vaccinated) 69 JIA patients, (unvaccinated) |
Vaccinated: 38 NSAIDs 29 MTX 6 anti-TNFα 3 anti-IL1-R 2 oral GC 1 leflunomide Unvaccinated: 36 NSAIDs 31 MTX 4 anti-TNFα 2 anti-IL1-R 1 oral GC 1 leflunomide |
1B | All vaccinated patients had protective antibody levels against MMR, with a significant increase in GMC. Two patients became seronegative over time. | No MMR infections induced by vaccine. Frequency of flares was similar in vaccinated and unvaccinated patients. Patients on biologics did not show any MMR infections, flares or increase in disease activity. |
| Varicella zoster virus | |||||
| Pileggi et al. [17] | 17 JIA 4 JDM 4 other ARD 18 HC |
13 GC 4.2 mg/day 25 MTX 5 DMARD |
2B | Seroprotection 50 % in patients versus 72 % in HC (within range of historical healthy cohort). 2 of 8 patients that were exposed to VZV developed chickenpox, 1 of these patients was on anti-TNFα. |
3 patients with mild self-limiting VZV-like rash. No increase in disease activity. |
| Lu et al. [38] | 6 IBD | 6 6-MP 2 anti-TNFα |
4 | Seroprotection in 5/6 patients shortly after VZV vaccination. | No serious adverse events after primary/booster VZV vaccination, despite anti-TNFα usage. |
| Barbosa et al. [13••] | 28 JSLE patients (vaccinated) 26 JSLE patients (unvaccinated) 28 HC |
Vaccinated: 27 HCQ 18 GC (mean dose 7.5 ± 3.9 mg) 9 AZA 2 MTX Unvaccinated: 22 HCQ 18 GC (mean dose 9.4 ± 4.8) 12 AZA 2 CFM |
1B | Patients showed a similar increase in GMT as healthy controls. NB: seroprotection 100 % in patients and controls before vaccination. |
Frequency of flares was similar in vaccinated and unvaccinated patients. |
| Non-live composite | |||||
| Human papilloma virus | |||||
| Soybilgic et al. [52] | 27 JSLE | 27 HCQ 16 GC (mean dose 12.6 mg) 9 AZA 9 MMF 6 MTX |
3 | All but one patient seroconverted for all 4 HPV types. | No increase in disease activity after vaccination. |
| Heijstek et.al. [16] | 6 JSLE 6 JDM 49 HC |
6 GC 2 HCQ 2 MTX 1 AZA 1 MMF |
2b | All but one JDM patient and all controls seroconverted after the third dose. The GMT in patients was lower than in HC. | No increase in disease activity after vaccination. |
| Heijstek et al. [15] | 68 JIA 55 HC |
37 NSAIDs 24 MTX 9 anti-TNFα 6 other DMARDs 1 anti-IL-1R |
2b | All participants were seropositive after vaccination. The GMT in patients was lower than in HC. | No disease flares, no increase in disease activity after vaccination. |
| Hepatitis A virus | |||||
| Beran et al. [53] | 10 AIH | Unknown | 3 | 100 % response rate. | No severe adverse events. No increase in disease activity. |
| Erguven et al. [40] | 47 JIA 67 HC |
12 GC 29 MTX 11 GC + MTX 19 sulphasalazine 4 anti-TNFα |
2B | 4 patients on anti-TNFα (systemic JIA) negative for anti-HAV antibodies after vaccination. 100 % response rate in all other patients and HC. | No adverse events. No increase in disease activity. |
| Moses et al. [54] | 12 pIBD | 12 anti-TNFα 2 MTX |
3 | Seroconversion rate was 92 %. | – |
| Hepatitis B virus (DNA) | |||||
| Kasapçopur et al. [26] | 39 JIA 41 HC |
20 GC 22 MTX |
2B | Seroprotection in 38/39 patients vaccination, comparable to HC. No effect IS drugs. | No increase in disease activity. |
| Beran et al. [53] | 10 AIH | Unknown | 3 | 100 % response rate in patients <15 years. 50 % response rate in 4 patients aged 16–20 year, 1 used GCs 5 mg/day. |
No severe adverse events. No increase in disease activity. |
| Aytac et al. [30] | 20 JSLE 24 HC |
17 GC (mean dose 6.25 mg/day) 11 AZA 3 MMF 2 HCQ 3 no medication |
2B | Seroconversion and seroprotection lower in patients than in controls (80 versus 100 %). The GMT in patients was lower than in HC. | No increase in disease activity after vaccination. |
| Moses et al. [21] | 87 pIBD, of whom 34 received booster vaccine | 87 anti-TNFα (mean 6.9 ± 1.8 mg/kg/dose) 53 AZA 36 MTX 14 6-MP |
3 | 56 % of patients were protected after HBV vaccination in the past; 76 % of 34 patients had an adequate response to the booster vaccine. | – |
| Maritsi et al. [19] | 89 newly diagnosed JIA 89 HC |
None: study measured protective antibody levels from NVP | 2B | After a median time after vaccination of 5 years, the level of protective anti-HBs-antibody levels was significantly lower in JIA patients (55 %) than in HC (92 %). | – |
| Seasonal influenza | |||||
| Denman et al. [55] | 3 JIA 20 HC |
3 chlorambucil | 2B | Similar anti-influenza antibody concentrations. No effect of IS drugs. | – |
| Malleson et al. [43] | 34 JIA 13 HC |
7 GC 9 DMARD |
2B | Similar anti-influenza antibody concentrations and seroconversion rate as HC. No effect of IS drugs. | Similar adverse events as healthy controls. 4 flares per 145 patient months before versus 3 flares per 34 patient months after vaccination. As a group, more patients improved than deteriorated. |
| Kanakoudi-Tsakalidou et al. [25] | 49 JIA 11 SLE 3 JDM 7 other ARD 5 HC |
16 GC 16 GC + MTX 11 GC + CY 6 GC + AZA 8 GC + MTX + CY 5 MTX 4 CY 4 MTX + CY |
2B | 15 non-responders among patients. Similar immunogenicity between patients. |
No severe adverse events. No increase in disease activity. |
| Mamula et al. [56] | 51 IBD 29 HC |
12 GC 1 MTX 18 6-MP 10 6-MP + anti-TNFα 6 MTX + anti-TNFα |
2B | In general, lower responses to 1 strain compared with HC. Lower responses in patients on anti-TNFα + DMARDs towards 2 strains. | Similar non-severe adverse events as HC. No increase in disease activity. |
| Lu et al. [28] | 146 IBD | 12 GC 59 MTX/AZA/6-MP 45 anti-TNFα 10 tacrolimus |
3 | In general good immunogenicity. Patients on anti-TNFα lower responses to 1 strain in contrast to other IS drugs. | No severe adverse events. No increase in disease activity. |
| Ogimi et al. [29] | 23 JIA 12 SLE 6 JDM 2 KD 2 MCTD 4 other ARD 36 HC |
14 GC 7 GC + MTX 7 GC + MMF 4 GC + other DMARD 13 GC + 2 DMARD 2 CY 1 MTX 1 MTX + CFM + AZA |
2B | Similar anti-influenza antibody concentrations and seroconversion rate as HC. No effect of IS drugs. Of note, pre-vaccination anti-influenza antibody concentrations were higher in patients. | Similar non-severe adverse events as HC. 2 patients (1 JIA, 1 Takayasu arteritis) experienced a flare of disease within 2 weeks after vaccination. |
| Woerner et al. [35] | 25 JIA 3 uveitis 2 IBD 2 RMO 1 vasculitis 1 JSLE 1 MCTD 16 HC |
18 MTX 10 anti-TNFα 8 MTX + anti-TNFα |
2B | Seroprotection and seroconversion were similar in patients and controls. The GMT in patients was lower than in HC. | – |
| Dell’Era et al. [41] | 60 JIA 30 HC |
30 DMARD (unspecified) 32 MTX 30 anti-TNFα |
2B | Seroprotection and seroconversion were similar in patients treated with DMARDs and controls. | No increase in disease activity after vaccination. |
| Shimizu et al. [57] | 1 soJIA | 1 anti-IL6 | 3 | – | Case report of disease flare after influenza vaccination. |
| Shinoki et al. [42] | 27 soJIA 17 HC |
27 anti-IL6 24 GC (mean dose 7.3 mg/day) |
2B | Seroconversion, seroconversion and GMT were similar to healthy controls. | No increase in disease activity after vaccination. |
| Toplak et al. [24] | 31 JIA (vaccinated) 31 JIA (unvaccinated) 17 HC |
18 without therapy 7 DMARD + GC (<10 mg/day) 4 anti-TNFα 3 leflunomide 2 sulphasalazine |
2B | Seroprotection similar to controls after 1 month, similar decline in protective antibodies after 6 months. | Flare rate in vaccinated group 36 %, in unvaccinated group 23 %, but the unvaccinated group had less active disease and selection of control group unclear. |
| Aikawa et al. [31]a | 99 JSLE 93 JIA 18 JDM 11 JScl 16 vasculitis 91 HC |
54 GC <20 mg/day 36 GC ≥20 mg/day 74 MTX 43 AZA 23 CY 13 MMF 6 leflunomide 3 CFM |
2B | Compared to HC, seroconversion, seroprotection and GMT were significantly lower in JSLE patients and lower in other pedRD. | – |
| Guissa et al. [58]a | 30 JDM 81 HC |
12 GC <20 mg/day 3 GC ≥20 mg/day 14 MTX 7 HCQ 6 CY 2 AZA |
2B | Similar seroprotection rate in patients and controls. NB: 12 of these patients are also included in study of Aikawa et al. 2012. |
No disease flares, no increase in disease activity after vaccination. |
| Aikawa et al. [36]a | 95 JIA 91 HC |
63 DMARD/IS (prednisone, leflunomide, CFM sulphasalazine) 47 MTX 16 anti-TNFα |
2B | Significantly lower seroconversion in patients, similar seroprotection and GMT in patients and controls. NB: patients in this study are also included in study of Aikawa et al. 2012. |
No disease flares, no increase in disease activity after vaccination. |
| Campos et al. [32] | 110 JSLE 102 HC |
92 antimalarials 43 GC <20 mg/day 40 GC ≥20 mg/day 44 AZA 15 MMF 14 MTX 3 CFM 2 CY |
2B | Seroconversion, seroprotection and GMT were significantly lower in patients than in controls. A SLEDAI >8 was associated with non-response in multivariate analysis. |
No increase in disease activity after vaccination. |
| Carvalho et al. [23] | 44 JIA 10 HC |
31 MTX or leflunomide 6 GC (mean dose 0.3 mg/kg/day) 5 anti-TNFα 1 CY |
2B | Seroprotection in patients similar to controls. | No increase in disease activity after vaccination. |
| Meningococcal (MenC) | |||||
| Zonneveld-Huijssoon et al. [59] | 234 JIA | 36 MTX <10 mg/m2/week 15 MTX >10 mg/m2/week 7 sulphasalazine 8 anti-TNFα 1 CFM 2 MTX + sulphasalazine |
2B | In general, good protection in all JIA patients. Lower MenC-specific antibody responses in patients receiving IS drugs, but sufficient bactericidal activity as patients with high responses towards the MenC vaccination. | No increase in disease activity, no increased risk of a relapse after vaccination. |
| Stoof et al. [22] | 127 JIA 1527 HC |
108 MTX 60 biologicals 14 GC |
2C | Highest post-vaccination antibody concentrations were seen in the eldest patients at time of vaccination. Antibody levels waned over time in all patients. The persistence over time was similar to healthy controls. | – |
| Pneumococcal (PCV7) | |||||
| Farmaki et al. [39] | 63 JIA | 32 DMARD ± C 31 DMARD + anti-TNFα ± GC |
2B | Lower antibody concentrations against 3/7 serotypes, but similar response and protection rate. No pneumococcal disease or respiratory tract symptoms during 2-year follow-up | No increase in disease activity. Similar mild adverse events in patients with and without anti-TNFα. |
| Tetanus-diphtheria | |||||
| Denman et al. (TT vaccine) [55] | 3 JIA 20 HC |
3 chlorambucil | 2B | Similar anti-TT antibody concentrations. No effect of IS drugs. |
– |
| Höyeraal et al. [60] | 34 JIA 34 HC |
Unknown | 3 | Higher antibody humoral responses to TT and diphtheria, although not corrected for higher baseline antibody levels. | – |
| Kashef et al. (TT vaccine) [61] | 40 SLE 60 HC |
10 GC + CFM 13 GC + AZA 5 GC + CFM + AZA 8 GC + MMF |
3 | Several years after vaccination, similar seroprotection rate (100 %) against TT. Influence IS drug unknown. | – |
| Miyamoto et al. (TT vaccine) [20] | 30 JSLE 14 HC |
25 HCQ 19 oral GC 14 AZA 9 I.V. GC 2 CFMpulse 2 CY 2 MTX 1 MMF |
2B | Patients had protective antibody levels of tetanus antibodies than controls. No effect of IS drugs. | – |
| Heijstek et al. (TD vaccine) [18] | 400 JIA 2176 HC |
246 NSAID 93 MTX 28 oral GC (median dose 10 mg/day) 24 DMARD 8 anti-TNFα |
2C | Protective antibody levels against diphtheria and tetanus in patients were lower after past vaccination (time since vaccination up to 10 years; adjusted OR for seroprotection between 0.1 and 0.4). | |
Adapted from Heijstek et al. Vaccination in paediatric patients with auto-immune rheumatic diseases: a systemic literature review for the European League against Rheumatism evidence-based recommendations, Autoimmunity reviews 2011;11;112–122
AIH auto-immune hepatitis patient, ARD auto-immune rheumatic disease, AZA azathioprine, BCG Bacillus Calmette-Guérin, CFM cyclophosphamide, CY cyclosporine A, DMARD disease-modifying anti-rheumatic drug, GC glucocorticosteroids, GMC geometric mean concentration, GMT geometric mean titres, HAV hepatitis A virus, HBV hepatitis B virus, HC healthy controls, HCQ hydroxychloroquine, HPV human papillomavirus, IBD inflammatory bowel disease patient, IL6 interleukin-6, IS immunosuppressive, ITP idiopathic thrombocytopenic purpura patient, JDM juvenile dermatomyositis patient, JIA juvenile idiopathic arthritis patient, JScl juvenile scleroderma patient, JSLE juvenile systemic lupus erythematosus patient, KD Kawasaki disease patient, LoE level of evidence, 6-M 6-mercaptopurine, MenC meningococcal serogroup C conjugate vaccine, MCTD mixed connective tissue disease patient, MMF mycophenolate mofetil, MMR measles, mumps, rubella, MTX methotrexate, NSAID non-steroid anti-inflammatory drugs, NVP national vaccination programme, OR odds ratio, PCV7 7-valent pneumococcal conjugate vaccine, pedRD paediatric rheumatic diseases, pIBD paediatric inflammatory bowel disease patient, PPD purified protein derivative of tuberculin, RMO recurrent multifocal osteomyelitis patient, soJIA systemic onset juvenile idiopathic arthritis patient, TD tetanus-diphtheria vaccine, TNFα tumour necrosis factor alpha, TT tetanus toxoid, VZV varicella zoster virus
aThese studies overlapped in patient population