University of Groningen
Immunity to varicella-zoster virus in immunocompromised patients
Rondaan, Christien
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Rondaan, C. (2018). Immunity to varicella-zoster virus in immunocompromised patients. University of
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Proposal for updated
recommendations for vaccination in adult
patients with autoimmune inflammatory
rheumatic diseases
Christien Rondaan, Marc Bijl, Sander van Assen
Manuscipt in preparationABSTRACT
Aim
To update the 2011 evidence-based recommendations of the European League Against
Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune
inflammatory rheumatic diseases (AIIRD).
Methods
We performed the systematic literature review of reports published on specific vaccines
in AIIRD between from October 2009 to April 2017, using MedLine, addressing efficacy
and safety. After discussing results within the task force, we formulated a proposal for
updated recommendations. Grading of Recommendations Assessment, Development and
Evaluation (GRADE) criteria were used to assess methodological quality of the studies.
Evidence was graded in categories 1-4 and the strength of recommendations was graded
in categories A-D.
Results
Most vaccines seem efficacious in patients with AIIRD, although some are less efficacious
than in healthy control subjects and/or during treatment with immunosuppressive agents.
Six recommendations were proposed and presented alongside with category of strength
and underlying evidence.
Conclusion
The currently available evidence regarding efficacy of vaccination in AIIRD was summarized
and a proposal for updated evidence-based recommendations was formulated. Our work
and the work of other members of the Task Force will be joined, integrating data on
incidence of vaccine-preventable infections and on efficacy and safety of vaccination in
patients with an AIIRD into one manuscript.
8
INTRODUCTION
Patients with an auto-immune inflammatory rheumatic disease (AIIRD) are at increased
risk of contracting infections and associated complications. Increased susceptibility is
most likely due to the immune modulating effect of the disease itself and/or by use of
immunosuppressive medication [1].
Vaccination is generally regarded as a safe, efficacious and low-cost method for
preventing certain infections. However, vaccination may be less efficacious in (subgroups
of) patients with an AIIRD, as a result of their immunosuppressed state, and, moreover,
could potentially lead to exacerbation of the underlying AIIRD by aspecifically triggering
the immune system.
In 2011 recommendations for vaccination in AIIRD patients were published, based on
the available evidence and formulated by a European League Against Rheumatism (EULAR)
task force, to aid physicians and nurses dealing with questions regarding vaccination in
AIIRD in daily clinical practice [2]. At the time, it was stated that the recommendations
needed to be updated on a regular basis as new evidence will keep coming available [2].
The aim of the current project was to review new literature on vaccination in patients
with AIIRD, published since the previous recommendations, in order to formulate
a proposal for updated recommendations.
METHODS
A systematic literature review of the newly available evidence published since the last
guidelines was performed by members of an international task force consisting of
experts from European countries and Israel. We here describe the results of the review
on specific vaccines (Table 1) in AIIRD patients with regard to efficacy. Others investigated
the incidence of vaccine-preventable diseases in AIIRD and safety of vaccination in this
patient group, which will be published elsewhere.
Based on a previously applied strategy [2,3], AIIRD conditions and vaccines were used
as search terms (Table 1), using MedLine (via PubMed; from October 2009 to April 2017).
Eligible papers must be in English and include patients of at least 16 years of age. Case
reports and case series with five or fewer patients were not included. When relevant
according to the opinion of the experts, additional papers could be added. Articles were
first selected
based on title, and could later be excluded by abstract or text. Scoring
was done as described in Table 2, according to EULAR standard operating procedures [4].
Methodological quality of the studies was assessed by CR, in consensus with SvA when
needed, using Grading of Recommendations Assessment, Development and Evaluation
(GRADE) criteria [5].
After presenting and discussing results from the literature review in the international
expert group, a proposal for updated recommendations was formulated. Strength of
recommendations was established according to Table 3, conform EULAR standard
operating procedures [4]. For every proposed recommendation level of evidence and
strength of recommendation is presented separately with regard to efficacy and safety.
RESULTS
Hereunder the recommendations as proposed by the EULAR Task Force on Vaccination in
Adult Patients with AIIRD can be found, followed by a summary of the evidence found by
the systemic literature review.
1. Influenza vaccination should be strongly considered for patients
with AIIRD; level of evidence (efficacy/safety)1A/1A, strength of
recommendation (efficacy/safety) A/A. (Table 4A and 4B)
Seasonal trivalent influenza vaccination has been shown to reduce incidence and bacterial
complications of influenza, admissions for and mortality from influenza/pneumonia in
AIIRD [6-9]. It has been shown to be efficacious in patients with rheumatoid arthritis (RA),
Table 1. AIIRD and vaccines considered in the literature search*.
AIIRD Vaccines
Rheumatoid arthritis Bacillus Calmette-Guérin
Systemic lupus erythematosus Cholera
Antiphospholipid syndrome Diphtheria
Adult Still disease Hepatitis A
Systemic sclerosis Hepatitis B
Sjögren’s syndrome Haemophilus influenzae b
Mixed connective tissue disease Human papillomavirus
Relapsing polychondritis Influenza
Giant cell arteritis Japanese encephalitis
Polymyalgia rheumatica Measles
Takayasu arteritis Mumps
Polyarteritis nodosa Neisseria meningitides
ANCA-associated vasculitis: Pertussis
Microscopic polyangiitis Poliomyelitis
Granulomatosis with polyangiitis Rabies
(Wegener’s granulomatosis) Rubella
Eosinophilic granulomatosis with Tetanus toxoid
polyangiitis (Churg-Strauss syndrome) Tick-borne encephalitis
Behçet disease Typhoid fever
Goodpasture syndrome Varicella zoster
Cryoglobulinemic syndrome Yellow fever
Polymyositis Dermatomyositis
Clinically amyopathic dermatomyositis Sporadic inclusion body myositis
8
Table 1. (continued) AIIRD Vaccines Anti-synthetase syndrome Eosinophilic myositis Eosinophilic fasciitis Spondylarthropathies Periodic fever syndromesAbbreviations: AIIRD: auto-immune inflammatory rheumatic disease * Search terms:
(AIIRD:) “Lupus Erythematosus, Systemic”[MeSH Terms] OR “lupus”[Tiab] OR “Antiphospholipid Syndrome”[MeSH Terms] OR “antiphospholipid syndrome”[Tiab] OR “Arthritis, Rheumatoid”[MeSH Terms] OR “rheumatoid arthritis”[Tiab] OR “Still’s Disease, Adult-Onset”[MeSH Terms] OR “Still’s”[Tiab] OR “Scleroderma, Systemic”[MeSH Terms] OR “scleroderma”[Tiab] OR “Sjogren’s Syndrome”[MeSH Terms] OR Sjogren [Tiab] OR “Mixed Connective Tissue Disease”[MeSH Terms] OR “Mixed Connective Tissue Disease”[Tiab] OR “Polychondritis, Relapsing”[MeSH Terms] OR “Polychondritis”[Tiab] OR “Giant Cell Arteritis”[MeSH Terms] OR “Giant Cell Arteritis”[Tiab] OR “Polymyalgia Rheumatica”[MeSH Terms] OR “Polymyalgia Rheumatica”[Tiab] OR “Takayasu Arteritis”[MeSH Terms] OR “Takayasu”[Tiab] OR “Polyarteritis Nodosa”[MeSH Terms] OR “Polyarteritis”[Tiab] OR “Microscopic Polyangiitis”[MeSH Terms] OR “Granulomatosis with Polyangiitis”[MeSH Terms] OR “Polyangiitis”[Tiab] OR “Wegener”[Tiab] OR “Churg-Strauss Syndrome”[MeSH Terms] OR “Churg-Strauss”[Tiab] OR “Behcet Syndrome”[MeSH Terms] OR “Behcet*”[Tiab] OR “Anti-Glomerular Basement Membrane Disease”[MeSH Terms] OR “Anti-Glomerular Basement Membrane Disease”[Tiab] OR “Cryoglobulinemia”[MeSH Terms] OR “Cryoglobulinemia”[Tiab] OR “Polymyositis”[MeSH Terms] OR “Polymyositis”[Tiab] OR “Dermatomyositis”[MeSH Terms] OR “Dermatomyositis”[Tiab] OR “Myositis, Inclusion Body”[MeSH Terms] OR “Myositis”[Tiab] OR “Anti-synthetase syndrome”[Tiab] OR “Anti“Anti-synthetase syndrome”[Tiab]OR “Fasciitis”[MeSH Terms] OR “Fasciitis”[Tiab] OR “Spondylarthropathies”[MeSH Terms] OR “Spondylarthropath*”[Tiab] OR “Hereditary Autoinflammatory Diseases”[MeSH Terms] OR “Autoinflammatory”[Tiab] OR “Periodic fever, familial, autosomal dominant” [Supplementary Concept] OR “Familial Mediterranean Fever”[MeSH Terms] OR “Familial Mediterranean Fever”[Tiab] AND (Vaccines:) “Herpes Zoster Vaccine”[MeSH Terms] OR “Herpes Zoster Vaccin*”[Tiab] OR “Shingles vaccin*”[Tiab] OR “Zoster vaccine*”[Tiab] OR “Papillomavirus Vaccines”[MeSH Terms] OR “HPV vaccine” [Tiab] OR “Papillomavirus vaccine*”[Tiab] OR “hepatitis b vaccines”[MeSH Terms] OR “hepatitis B vaccin*”[Tiab] OR “influenza vaccines”[MeSH Terms] OR “influenza vaccin*”[Tiab] OR “haemophilus influenzae vaccines”[MeSH Terms] OR “haemophilus”[Tiab] OR “tetanus toxoid” [Tiab] OR “bcg vaccine”[MeSH Terms] OR “cholera vaccines”[MeSH Terms] OR “diphtheria tetanus vaccine”[MeSH Terms] OR “diphtheria tetanus pertussis vaccine”[MeSH Terms] OR “diphtheria tetanus acellular pertussis vaccines”[MeSH Terms] OR “diphtheria toxoid”[MeSH Terms] OR “diphteria vaccin*”[Tiab] OR “diphteria toxoid”[Tiab] OR “hepatitis a vaccines”[MeSH Terms] OR “hepatitis a vaccin*”[Tiab] OR “Rabies vaccine”[MeSH Terms] OR “Rabies vaccines”[MeSH Terms] OR “rabies human diploid cell vaccine”[MeSH Terms] OR “rabies”[Tiab] OR “japanese encephalitis vaccines”[MeSH Terms] OR “japanese encephalitis vaccin*”[Tiab] OR “measles vaccine”[MeSH Terms] OR “mumps vaccine”[MeSH Terms] OR “meningococcal vaccines”[MeSH Terms] OR “pertussis vaccine”[MeSH Terms] OR “rubella vaccine”[MeSH Terms] OR “measles vaccin*”[Tiab] OR “mumps vaccin*”[Tiab] OR “meningococcal vaccin*”[Tiab] OR “pertussis vaccin*”[Tiab] OR “rubella vaccin*”[Tiab] OR “tick borne encephalitis vaccin*”[Tiab] OR “typhoid paratyphoid vaccines”[MeSH Terms] OR “*typhoid vaccin*”[Tiab]
systemic lupus erythematosus (SLE), ANCA-associated vasculitis (AAV), systemic sclerosis
(SSc) and psoriatic arthritis (PsA), even when treated with conventional disease modifying
anti-rheumatic drugs (cDMARDs), anti-tumour necrosis factor (TNF) alpha, tocilizumab
or tofacitinib, although some studies (including one meta-analysis [10]) show a modestly
reduced efficacy in SLE patients or in RA patients treated with anti-TNF or methotrexate
Table 2. Categories of evidence [4]. Category Evidence
1A From meta-analysis of randomised controlled trials 1B From at least one randomised controlled trial
2A From at least one controlled study without randomisation 2B From at least one type of quasi-experimental study
3 From descriptive studies, such as comparative studies, correlation studies or case-control studies
4 From expert committee reports or opinions and/or clinical experience of respected authorities
Table 3. Strength of recommendations [4]. Strength Directly based on
A Category I evidence
B Category II evidence or extrapolated recommendation from category I evidence C Category III evidence or extrapolated recommendation from category I or II evidence D Category IV evidence or extrapolated recommendation from category II or III evidence
(MTX) [11-46]. The use of rituximab was associated with reduced antibody responses
[10,47-50], but did not seem to affect cell-mediated immune responses in one study with
a limited number of patients [50]. Interestingly, temporary discontinuation of MTX was
shown to improve immunogenicity of seasonal influenza vaccination in patients with RA,
with the best results when MTX was suspended for 2 weeks before and 2 weeks after
vaccination [51]. Adverse events of influenza vaccination in patients with AIIRD were
found to be comparable to those in healthy controls, although there are no studies that
are sufficiently powered with regard to safety
[12,17,21,23-26,28,30-33,36-39,41,43-45,47,48,50,52-56].
Most larger studies investigating efficacy and safety of the pandemic monovalent
influenza vaccine found reduced efficacy in AIIRD patients (mostly RA and SLE) and on
most immunosuppressive medication, although protective antibody levels were reached
in the majority of patients [38,46,57-72]. The use of rituximab and abatacept is an
exception as this was associated with reduced antibody responses [61,73,74]. A second,
booster dose of vaccine was shown to improve efficacy, reaching levels of seroprotection
comparable to healthy controls [58,74,75]. This has also been shown in SLE-patients who
received seasonal influenza-vaccine for the first time [76]. Therefore, for AIIRD patients
naive for a certain influenza subtype, a second, booster vaccination can be considered.
Following vaccination, disease activity was stable in the majority of studies and only mild
adverse events were found [38,46,57-64,67-72,74,75,77-79].
8
Ta b le 4 A . E ffi ca cy a nd s af et y o f s ea so na l t riva le nt in flu enz a-va cc in at io n in A IIR D -p at ie nt s* Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Hua [10] 2014 Meta-analysis 7 studies†† See right Reduced in R TXFor MTX, results dif
fered
depending on method of analysis
NA 1A Moderate Chalmers [32] 1994 RCT 64 RA-PV No dif fer ence No No dif fer ence 1B 22 RA not-PV 40 RA-IS 64 HC Kaine [12] 2007 RCT 99 RA-ADA No dif fer ence No No flar es 1B 109 RA Kivitz [52] 2014 RCT 107 RA-CZP No dif ference Reduced on MTX No dif ference 1B High 109 RA-PCB Winthrop [34] 2016 RCT Tw o
independent parts Part A: 102 RA-TFC 98 RA-PCB Part B: 92 RA-TFC cont. 91 RA-TFC withdrawn Part A: similar proportions of satisfactory response Part B: No dif
ference
Part A: Reduced in TFC/ MTX Part B: No
NA 1B High Denman [13] 1970 Contr olled 20 RA 39 RA-DC 20 HC No dif fer ence No NA 2
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Kapetanovic [14] 2007 Contr olled
50 RA-anti- TNF+MTX 62 RA-anti- TNF+DMARD 37 RA-MTX 18HC Reduced in RA-anti- TNF+MTX and RA- anti-TNF compar
ed to
RA-MTX
Reduced on TNF+MTX and anti-TNF compar
ed to MTX NA 2 Kubota [15] 2007 Contr olled 27 RA-anti-TNF 36 RA-DC 52 HC No dif fer ence Incr eased on anti-TNF NA 2 Or en [48] 2008 Contr olled 29 RA 14 RA-R TX 21 HC Reduced in RA-R TX Reduced on R TX No flar es 2 Nii [16] 2009 Contr olled 27 RA-anti-TNF 36 RA-DC 52 HC No dif fer ence No NA 2 van Assen [47] 2010 Contr olled 23 RA-R TX 20 RA-DC 29 HC Reduced in RA-R TX Reduced on R TX No flar es 2 Fomin [17] 2006 Contr olled 82 RA 30 HC No dif fer ence No No flar es 2 Gelinck [18] 2008 Contr olled 64 anti-TNF* 48 non-anti- TNF** No dif fer ence
Reduced (modestly) on anti-TNF
NA
8
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Arad [50] 2011 Controlled 29 RA-R TX 17 RA-DC 16 HC Humoral immunity: reduced in RA-RTX
Similar percentage of influenza specific
IFN-γ
producing CD4+ cells in RA groups Humoral immunity:. Reduced on R
TX
Cellular immunity: No
No change disease activity
2A
Low
Tsuru [35] Abstract only
2013
Controlled
38 TCZ (28 RA/10 CD) 39 RA anti-TNF/ DMARD
No dif ference No NA 2A Low Herr on [19] 1979 Contr olled
20 SLE 17 RA 17 other AIIRD 32 HC
No dif fer ence Reduced on ster oids NA 2 Tur ner -Stokes [20] 1988 Contr olled 28 SLE 10 RA 4 MCTD 2 RA/SLE Reduced in SLE, MCTD
and RA/SLE
No
NA
2
Stojanovich[36] 2006 Contr olled23 SLE-vacc 46 SLE-DC 23 RA-vacc 31 RA Reduction in pneumonia, acute bronchitis or viral infections in SLE-vacc and RA-vacc
NA
No flar
es
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Del Porto [21] 2006 Contr olled
14 SLE 10 SLE-DC 10 RA 10 RA-DC
No dif fer ence NA No dif fer ence 2 Elkayam [53] 2009 Contr olled
20 RA-anti-TNF 23 RA-DC 18 SpA-anti-TNF
17 HC
No dif
fer
ence
No
No flar
es
2
Kobie [106] 2011 Controlled61 RA-anti-TNF 70 RA-MTX 33 RA-DC 97 HC Reduced in RA-anti- TNF Reduced on anti-TNF NA 2A Low Milanovic [54] 2013 Controlled
19 SLE–vacc. 11 SLE 15 RA-vacc. 22 RA 13 SjS-vacc. 19 SjS
Sign. dif
ference in
GMT between vacc./ unvacc.SLE, but not in RA and SjS Lower incidence influenza or bact. complications among vacc. patients
No
No changes disease activity
2A
V
ery low
Milanetti [38] Both seasonal and pandemic
2014 Controlled 30 RA 13 HC No dif ference No ef fect of anti-TNF or abatacept
More mild AE in patients
2A Low Anderson [107] 2012 Observational 13 RA-previous anti-CD52 Able to respond to vaccination
NA NA 3 V ery low Kobashigawa [9] 2013 Observational 17735 RA in 4 seasons V
accination associated with reduced risk influenza
No
NA
3
8
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Kogure [108] 2014 Observational 57 RA Seroprotection: H1N1 63%, H3N2 81%, influenza B 26% Reduced on biologicalsNo change disease activity
, no AE 3 Low Liao [37] 2016 Meta-analyis
18 studies with 1966 SLE 1116 HC Reduced in SLE for H1N1 and H3N2, but not for influenza B Respective seroprotection: 68%, 76%, 66%
NA No dif ference 32 mild flare, 5 serious AE 1A High W illiams [23] 1978 RCT 19 SLE 21 SLE-DC 36 HC Reduced in SLE Not on ster oids No dif fer ence 1B Ristow [24] 1978 Contr olled 29 SLE 29 HC No dif fer ence Not on ster oids/IS 1 glomer o-nephritis 2 Br odman [25] 1978 Contr olled 46 SLE No dif fer ence
Not on HCQ, AZA, PRED
No dif fer ence 2 Louie [26] 1978 Contr olled 11 SLE 8 HC No dif fer ence NA 1 glomer o-nephritis 2 Pons [27] 1979 Contr olled 11 SLE 12 HC No dif fer ence NA NA 2 Abu-Shakra [28] 2002 Contr olled 24 SLE 24 SLE-DC Reduced in SLE Reduced on AZA No flar es 2 Mer cado [29] 2004 Contr olled 18 SLE 18 HC Reduced in SLE No NA 2 Holvast[30] 2006 Contr olled 56 SLE 18 HC Reduced in SLE Reduced on AZA No flar es SLE mor e syst. AE 2
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE W allin [39] 2009 Controlled 47 SLE 27 HC No dif ference seroprotection Reduced on steroids
Overall stable disease
2A Low Wiesik- Szewczyk [40] 2010 Controlled 67 SLE 47 HC Reduced in SLE Reduced on HCQ NA 2 Crowe [41] 2011 Controlled 72 SLE 72 HC No dif ference. More
high responses in African-American subjects.
Reduced on steroids
19.4%/26.4% flare 6/12 weeks postvacc. More low responders with flare at 6 week
2A Low Vista [55] 2012 Controlled 101 SLE 101 HC NA NA
Similar proportion new onset anticardiolipin antibodies
2A Low Kaur [109] 2015 Controlled 10 SLE 8 HC Higher avidity and neutralization capacities of antibodies in SLE
NA NA 2A V ery low Launay [42] 2013 Observational 27 SLE
Percentages of responders at day 30 are 55.5%, 18.5% and 55.5%, for H1N1, H3N2 and influenza B, respectively Increase in rheumatoid factor levels, after vacc.No flares.
2B
V
8
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Holvast [76] 2009 RCT 49 WG 23 WG-DC 49 HC No dif fer ence No No dif fer ence 1B Zycinska [33] 2007 Contr olled 35 WG 28 WG-DC 35 HC No dif fer ence No No flar es 2 Setti [56] 2009 Contr olled 46 SSc 20 HC No dif fer ence NA No flar es 2 Litinsky [43] 2012 Controlled 26 SSc 16 HC Increased in SSc for H1N1 No difference
for H3N2 and influenza B Increased on combination iloprost and calcium channel blockers for H1N1 and influenza B Overall stable disease
2A Low Polachek [44] 2015 Controlled 63 PsA 4 Pso 30 HC No dif ference No
Increased CRP in patients 4-6 weeks postvacc.
2A Low Caso [45] 2016 Controlled 25 PsA-vacc. 25-PsA DC NA NA Higher T ender
Joint Count and ESR after 1 month, more episodes mild symptoms in PsA- vacc.
2A
V
Ta b le 4 A . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Kostianovsky [46] 2012 Observational
74 systemic vasculitis 32 SSc 29 SLE 23 SjS 28 other AIIRD
No dif ference No 19 flares 3 Low
* Articles published since
the
2011 r
ecommendations ar
e in bold.
Abbr
eviations: IS: immunosuppr
essive drugs, LoE: level of evidence, PV
: pr
eviously vaccinated, HC: healthy contr
ols, ADA: adalimumab, DC: disease-contr
ol, AE: adverse
events, NA: not addr
essed, vacc: vaccinated, MTX: methotr
exate, AZA: azathioprine, HCQ: hydr
oxychlor
oquine, PRED: pr
edniso(lo)ne, CsA: cyclosporine, ET
A: etaner
cept,
CZP: certolizumab pegol, PCB: placebo, ABA: abatacept, TCZ: tocilizumab, TFC: tofacitinib, SSc: systemic scler
osis, jSLE: juvenile SLE, MCTD: mixed connective tissue
disease, SjS: Sjögr
en’
s syndr
ome, DM: dermatomyositis, PM: polymyositis, JIA: juvenile idiopathic arthritis, BD: Behçet’
s disease, P
APS: primary antiphospholipid syndr
ome,
PsA: psoriatic arthritis, Pso: psoriasis ††
The
seven studies included by Hua et al. that investigated influenza vaccine in RA: Fomin 2006, Kapetanovic 2007, Kaine 2007, Kivitz
2011, Kubote 2007, Or
en 2008,
Arad 2011.
* Gr
oup consisted of patients with RA (n=52), juvenile chr
onic arthritis (n=2), Still’
s disease (n=2), psoriatic arthritis (n=1), spondyloarthr
opathy (n=1) and Cr
ohn’
s disease
(n=6). ** Gr
oup consisted of patients with RA (n=27), juvenile chr
onic arthritis (n=2), psoriatic arthritis (n=3), Cr
ohn’
s disease (n=15) and inflammatory bowel disease (n=1).
‡ Gr
oup consisted of patients with SLE (n=572), RA (n=343), psoriatic arthritis (n=101), ankylosing spondylitis (n=152), Behçet’
s disease (n=85), dermatomyositis (n=45),
systemic scler
osis (n=127), mixed connective tissue disease (n=69), primary antiphospholipid syndr
ome (n=54), primary Sjögr en’ s syndr ome (n=36), T akayasu’ s arteritis (n=30), polymyositis (n=28), W egener’ s granulomatosis (n=26) † Gr
oup consisted of patients with cancer (n=319), RA (n=260), HIV
-infected (n=256), kidney transplant r
ecipients (n=85), juvenile idiopathic arthritis (n=83) and elderly
8
Ta bl e 4 B . E ffi ca cy a nd s af et y o f p an de m ic m on ova le nt ( H 1N 1) in flu enz a-va cc in at io n in A IIR D -p at ie nt s Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Saad [57] Nonadj. 2011 Contr olled 1668 AIIRD‡ 234 HC Reduced in AIIRD vs. HC Reduced in SLE and RANo
Overall stable disease
2A
Moderate
Gabay [58] Adj. (AS03)
2011
Contr
olled
82 RA 45 SpA 46 other AIIRD 138 HC Reduced in patients No dif
fer
ence after
2 doses in patients (ser
opr
otection
after 1 and 2 doses 75% and 85%, r
espectively)
Reduced on DMARDs and within 3 mo. after B cell depletion
Overall stable disease
2A Low Elkayam [59] Adj. (MF59) 2011 Contr olled 41 RA 21 SLE 17 PsA 15 AS 25 HC Reduced in RA/PsA patients Ser
opr
otection in
60-76% of patients
Reduced on leflunomide and infliximab
Overall stable disease
2A Low Ribeir o [60] Nonadj. 2011 Contr olled 340 RA 234 HC Reduced in RA Reduced on MTX Mor e local AE in HC. Mor e mild systemic AE in RA 2A Low
Adler [61] AS03 adjuvanted
2012
Contr
olled
47 RA 59 SpA 15 vasculitis 28 CTD 40 HC Reduced in patients (but not in SpA and CTD)
Reduced on ABA, RTX and MTX
No dif
fer
ence AE. Incr
ease
disease activity in 32 patients
2A Low França [62] Nonadj. 2012 Contr olled
41 RA-anti-TNF 79 SpA-anti-TNF 41 RA-DC 75 SpA-DC 117 HC Reduced in SpA-anti-TNF but not for etaner
cept
Reduced on MTX (RA). Reduced on anti-TNF (SpA) (except etaner
cept) Mor e mild systemic AE in patients on anti-TNF 2A Low
Ta bl e 4 B . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE
Iwamoto [63] Mostly nonadj.
2012
Contr
olled
89 RA 14 HC Reduced (nonsignificant) in RA Ser
opr
otection
55.1%
Lower (nonsignificant) on biologics
1 facial palsy 2A Low Ribeir o [73] Nonadj. Subanalysis of [60] 2013 Contr olled 11 RA-ABA 33 RA-MTX DC 55 HC Reduced in RA-ABA Reduced on ABA No dif fer ence 2A Low
Milanetti [38] Both seasonal and pandemic, adj. (MF59)
2014 Contr olled 30 RA 13 HC No dif fer ence No ef fect of anti-TNF or ABA Mor e mild AE in patients 2A Low Miraglia [64] Nonadj. 2011 Observational 1152 Immune- compr omised†: 260 RA 83 JIA Ser opr otection in 61.5%
of RA and in 85.5% of JIA patients
NA
Mild systemic AE in mor
e
than 20% of RA and JIA
3
Low
Kapetanovic [65] Adj. (AS03)
2014
Observational
50 RA-MTX 38 RA-anti-TNF 53 RA-anti- TNF+MTX 5 RA-ABA 10 RA-R
TX
2 RA TCZ 41 SpA-anti-TNF 51 SpA-anti- TNF+MTX Two doses in 58%
Reduced in RA-R TX Incr eased in SpA-anti-TNF Incr eased after
two doses, except for RA-MTX and RA-R
TX Reduced on R TX 1 pneumonia 3 Low
8
Ta bl e 4 B . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Lu [77] Nonadj. 2011 Contr olled 21 SLE 15 HC No dif fer ence NoChanges in autoantibody levels Overall stable clinical disease activity 1 flar
e
2A
Low
Ur
owitz [78]
Both adj. and nonadj.
2011
Contr
olled
103 SLE: 51 adj. 52 nonadj.
NA NA No dif fer ence
Overall stable disease
2A Low Aikawa [67] Nonadj. 2012 Contr olled 237 jAIIRD 91 HC Reduced in patients Reduced on ster oids Mor e arthralgia in patients. 2A Low Borba [68] Nonadj. 2012 Contr olled 555 SLE 170 HC Reduced in SLE with therapy (except for antimalarials) No dif
fer
ence HC and
SLE without therapy
Reduced for ster
oids and IS
Restor
ed
when using concomitant antimalarials Overall stable disease
2A Low Campos [69] Nonadj. 2013 Contr olled 118 jSLE 102 HC Reduced in SLE Seopr
otection in 73.7%
High SLEDAI associated with nonser
oconversion
No
Overall stable disease
2A Low Mathian [75] Nonadj. 2011 Observational 111 SLE Incr eased after
booster vaccination (ser
opr
otection after 1
and 2 doses 67% and 80%, r
espectively) Reduced on IS No sever e AE Overall stable disease 2B Low Shinjo [70] Nonadj. 2012 Contr olled 37 DM + 21 PM 116 HC No dif fer ence No No dif fer ence
Overall stable disease
2A
Ta bl e 4 B . (c on tin ue d) Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Miossi [71] Nonadj . 2013 Contr olled 69 MCTD 69 HC No dif fer ence No
Overall stable disease
2A Low Pasoto [72] Nonadj. 2013 Contr olled 36 SjS 36 HC No dif fer ence No No dif fer ence Significant incr
ease in mean levels of
anti-Ro/SSA and anti-La/ SSB after 1-year No change other auto-antibodies
2A Low De Medeir os [79] Nonadj. 2014 Contr olled 45 P APS 33 HC NA NA
No change in overall frequencies autoantibodies
2A
Low
Abbr
eviations: IS: immunosuppr
essive drugs, LoE: level of evidence, nonadj.: nonadjuvanted vaccine was used, adj.: adjuvanted vaccine was used, AIIRD: autoim
mune
inflammatory rheumatic diseases, HC: healthy contr
ols, SLE: systemic lupus erythematosus, RA: rheumatoid arthritis, SpA: spondyloarthritis, DMARD: disease modifying
antirheumatic drug, PsA: psoriatic arthritis, AS: ankylosing spondylitis, MTX: methotr
exate, AE: adverse events, TNF: tumor necr
osis factor
, DC: disease-contr
ol, CTD:
connective tissue disease, ABA: abatacept, JIA: juvenile idiopathic arthritis, NA: R
TX: rituximab, TCZ: tocilizumab, PRED: pr
ednis(ol)one, jSLE: juvenile SLE, SLEDAI: Systemic
Lupus Erythematosus Disease Activity Index,
DM: dermatomyositis, PM: polymyositis, MCTD: mixed connective tissue disease, SjS: Sjögr
en’ s syndr ome, P APS: primary antiphospholipid syndr ome, ‡ Gr
oup consisted of patients with SLE (n=572), RA (n=343), psoriatic arthritis (n=101), ankylosing spondylitis (n=152), Behçet’
s disease (n=85), dermatomyositis (n=45),
systemic scler
osis (n=127), mixed connective tissue disease (n=69), primary antiphospholipid syndr
ome (n=54), primary Sjögr en’ s syndr ome (n=36), T akayasu’ s arteritis
(n=30), polymyositis (n=28), Granulomatosis with polyangiitis (n=26) † Gr
oup consisted of patients with cancer (n=319), RA (n=260), HIV
-infected (n=256), kidney transplant r
ecipients (n=85), juvenile idiopathic arthritis (n=83) and elderly
8
2. Patients with AIIRDs should receive tetanus toxoid vaccination in
accordance to recommendation for the general population. Passive
immunization should be considered under B cell depleting therapy;
level of evidence 1B/1B, strength of recommendation A/A. (Table 5)
In patients with RA and SLE, efficacy for tetanus toxoid vaccination has been demonstrated
to be comparable with healthy controls [13,80-82]. This also holds true for patients with
RA on immunosuppressive drugs, including those who have been treated with rituximab
24 weeks earlier [83-85]. Patients with AIIRDs are therefore recommended to receive
tetanus toxoid vaccination in accordance to recommendations for the general population.
However, since no data are available regarding the efficacy of tetanus toxoid vaccine
within 24 weeks after treatment with B cell depleting therapy, passive immunization with
tetanus immunoglobulins should be considered in AIIRD patients under B cell depleting
therapy when tetanus toxoid vaccination is indicated.
3. Herpes zoster vaccination may be considered in high risk patients
with AIIRDs; level of evidence 2A/2A, strength of recommendation
B/B. (Table 6)
In a retrospective database study including patients with immune-mediated diseases (RA,
spondyloarthritis, psoriasis, inflammatory bowel diseases), it was shown that vaccination
with the live attenuated zoster vaccine is associated with a reduced incidence of herpes
zoster in patients over 60 years with an AIIRD. This effect was present regardless
medication use, including biologics. As the vaccine contains live attenuated virus,
the occurrence of VZV infection shortly after vaccination was a safety concern. Within
42 days after vaccination a reduced incidence of herpes zoster was seen in vaccinated
patients. Furthermore, no cases of hospitalized VZV-associated meningitis or encephalitis
were identified in this period [86]. The vaccine furthermore seemed to be immunogenic
and safe in a small sample of SLE patients [87], and in corticosteroid-treated persons
(mostly 5-10 mg daily, >10-20 mg daily in 25 vaccinated patients) [88]. However, large
prospective trials sufficiently powered for assessing safety of this live attenuated vaccine
in AIIRD-patients are lacking.
Of note, an adjuvanted subunit (non-live) vaccine has recently been shown to be safe
and more efficacious than the live attenuated vaccine in adults above the age of 50 and
70 years [89,90]. Safety and efficacy of the subunit zoster vaccine have not yet been
investigated in AIIRD patients.
4. Hepatitis A and B can be administered to AIIRD patients at risk; level
of evidence 2A/2A for hepatitis B (Table 7) and 2B/2B for hepatitis A,
strength of recommendation B/B.
Patients with AIIRD are recommended to receive vaccination for hepatitis A and/or B in
accordance to the national vaccination guidelines. It must be emphasised, however, that
Ta b le 5 . E ffi ca cy a nd s af et y o f t et an us va cc in at io n in A IIR D -p at ie nt s* Author Y ear Study design No. cases Ef ficacy Influence of IS on ef ficacy Safety LoE GRADE Bingham [85] 2015 RCT 60 RA-TCZ+MTX 31 RA-MTX DC No dif ference No Higher incidence of AE in TCZ+MTX 1B Moderate Bingham [84] 2015 RCT 73 RA-T ABA 25 RA-PCB No dif ference No NA 1B Moderate Denman [13] 1970 Contr olled 20 RA 39 RA-DC No dif fer ence No NA 2 Bingham [83] 2010 Contr olled 69 RA-R TX 34 RA-DC No dif fer ence No NA 2 Anderson [107] 2012 Observational 13 RA-previous anti-CD52 Seroprotection from 60% to 80% of patients
NA NA 2A Low Devey [80] 1987 Contr olled 24 SLE 29 RA 33 HC No dif fer ence NA NA 2 Abe [81] 1971 Contr olled 20 SLE 20 HC No dif fer ence No NA 2 Nies [110] 1980 Contr olled 9 SLE 9 HC Reduced in SLE NA NA 2 Kashef [82] 2008 Contr olled 40 SLE 60 HC No dif fer ence No NA 2 Battafarano [111] 1998 Uncontr olled 73 SLE 90% pr otection Tr end lower
response on PRED and AZA
NA
3
* Articles published since
the
2011 r
ecommendations ar
e in bold.
AIIRD: autoimmune inflammatory rheumatic diseases, IS: immunosuppr
essive drugs, LoE: level of evidence, RCT
: randomized contr
olled trial, RA: rheumatoid arthritis,
TCZ: tocilizumab, MTX: methotr
exate; HC: healthy contr
ols, DC: disease-contr
ol, AE: adverse events, T
ABA: tabalumab (anti-BAFF), PCB: placebo, NA: not addr
essed, R
TX:
rituximab, SLE: systemic lupus erythematosus, PRED: pr
8
Ta b le 6 . E ffi ca cy a nd s af et y o f h er pe s z os te r va cc in at io n in A IIR D -p at ie nt s Author Y ear Study design No. cases Ef ficacy Influence of IS on efficacy Safety LoE GRADE Russell [88] 2015 RCT206 CS HZ-vacc. (25% PMR) 100 CS PCB-vacc (31% PMR) mostly no AIIRD >10-20 mg: n=39 Higher postvaccination humoral r
eponse in
HZ-vacc.
No influence of limited daily GC dose
Mor
e injection-site
AE and headache in HZ-vacc. Other systemic and serious AE: no differ
ence 1B Moderate Guthridge [112] 2013 Contr olled 10 SLE 10 HC Similar pr oportion
of Subjects with 50% incr
ease in CMI measur es postvacc. NA No dif fer ence No flar es 2A Low Zhang [113] 2012 Observational
Total: 463,541* HZ-vacc: 18,683 (4.0%) HZ-vacc on biologics: 633 Lower incidence of HZ in vacc. patients
Lower HZ incidence in vacc. patients using biologics, DMARDs or GC alone HZ incidence <42 days after vacc. also decr
eased
No HZ <42 days in patients using biologics
3
Moderate
Abbr
eviations: IS: immunosuppr
essive drugs, LoE: level of evidence, HC: healthy contr
ols, DC: disease-contr
ol, NA: not addr
essed
AIIRD: autoimmune inflammatory rheumatic disease, CS: corticoster
oids, HZ: herpes zoster
, vacc.: vaccinated/vaccination, PMR: polymyalgia rheumatica, PCB: placebo,
CMI: cell-mediated immunity
, DMARD: disease-modifying antirheumatic drug, GC: glucocorticoid
* Patients with rheumatoid arthritis (n=292,169), psoriasis (n=89,565), psoriatic arthritis (n=11,030), ankylosing spondylitis
(n=4,026), and/or inflammatory bowel disease
Ta b le 7. E ffi ca cy a nd s af et y o f h ep at iti s B va cc in at io n in A IIR D -p at ie nt s* Author Y ear Study design No. cases Ef ficacy Influence of IS on efficacy Safety LoE GRADE Elkayam [93] 2002 Contr olled 22 RA 22 RA-DC 68% pr otection No No flar es 2 A ytac [96] 2011 Controlled 20 jSLE 24 HC Lower GMT in SLE but no significant dif
ference
80% protection
No
No significant overall change SLEDAI 15% flares
2A Low Kuruma [95] 2007 Uncontr olled 28 SLE 93% pr otection NA 11% flar es 3 Franco Salinas [114] 2009 Contr olled 20 SpA-anti-TNF 10 SpA-DC Reduced in SpA- anti-TNF Reduced on anti-TNF NA 2 Erkek [94] 2005 Contr olled 13 Behçet 15 HC No dif fer ence NA No 2
* Articles published since
the
2011 r
ecommendations ar
e in bold.
Abbr
eviations: IS: immunosuppr
essive drugs, LoE: level of evidence, HC: healthy contr
ols, DC: disease-contr
ol, NA: not addr
8
as opposed to strong immunogenicity in healthy individuals, a single dose of hepatitis
A vaccine does not seem to provide sufficient protection in RA patients [91], or in patients
using immunosuppressive drugs [92]. Regarding hepatitis A vaccination, a second
hepatitis A-vaccination after 6 months and determination of post-vaccination serology
is recommended. If this is not possible in the case of a last-minute traveller, an AIIRD
patient may not be protected after a single dose of vaccine and passive immunization for
the specific journey should be considered. Hepatitis B vaccination is efficacious in most
patients with AIIRD [93-96], see Table 7.
5. Human papilloma virus should be considered in AIIRD patients at
risk; level of evidence 2A/2A, strength of recommendation B/B.
HPV vaccination, with both bivalent or quadrivalent vaccine, is efficacious in (mostly
juvenile) female patients with AIIRD [97-100]. No studies addressing clinical endpoints of
HPV vaccination have been performed in AIIRD patients. Regarding safety, quadrivalent
HPV vaccine was not associated with increased incidence of new-onset autoimmune
disease in girls and women with pre-existing autoimmune disease [101].
HPV vaccination is recommended for young women in many countries, and should
especially be considered in young women with AIIRD as a higher occurrence of HPV
infection, also with oncogenic viral genotypes of the virus, has been shown in this
group [102-104].
6. AIIRD patients who plan to travel are recommended to receive
their vaccines according to general rules, except for live attenuated
vaccines; level of evidence NA, strength of recommendation D.
Two years after the inadvertent revaccination against Yellow Fever of 31 women with
AIIRDs (RA, SLE, SSc, ankylosing spondylitis), titres of neutralizing antibodies were
considered to be protective. Although no serious adverse events were reported [105],
Yellow Fever vaccine, like Bacillus Calmette-Guérin vaccine, oral poliomyelitis vaccine and
oral typhoid fever vaccine, might lead to life-threatening infection in immunosuppressed
patients as these vaccines contain live attenuated micro-organisms. With the exception
of these live attenuated vaccines and hepatitis A vaccine (as discussed under proposed
recommendation 4.), AIIRD patients who plan to travel should receive the vaccinations
that are recommended to the general population, to protect them from contracting
travel-related vaccine-preventable infections.
DISCUSSION
We here propose six recommendations for vaccination in AIIRD patients, in the context of
the update of the EULAR Recommendations on Vaccination in Adult Patients with AIIRD
as executed by a EULAR Task Force. These are based on the currently available evidence
regarding efficacy and safety as found by a systemic literature review and on a discussion
with international experts within the Task Force.
In formulating recommendations for vaccination, not only efficacy is of importance.
Indication for vaccination, evaluating incidence of vaccine-preventable infectious diseases
in AIIRD patients, is also essential to consider. Balancing pros and cons of vaccination is
only possible when risks of infectious diseases are also weighed.
Considering risk of vaccine-preventable infectious diseases in AIIRD patients is of extra
importance since studies were generally not sufficiently powered to assess the safety
of vaccination in this group. Theoretically, vaccination could lead to exacerbation of
the underlying AIIRD. Although many case reports and case series have been published
on this topic, in this literature review these were excluded as effects of vaccination could
not be distinguished from natural course of disease.
Concluding, the currently available evidence regarding efficacy of vaccination in
AIIRD was summarized and a proposal for updated evidence-based recommendations
was formulated. Our work and the work of the other members of the Task Force will be
joined. Data on incidence of vaccine-preventable infections and on efficacy and safety
of the corresponding vaccines, in the patient groups and during immunosuppressive
therapies included in the literature search, will be integrated into one manuscript.
8
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8
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