Accepted Manuscript

HLA-DRB1 alleles and juvenile idiopathic arthritis: Diagnostic

clues emerging from a meta-analysis

Annalisa De Silvestri, Cristina Capittini, Dimitri Poddighe, Gian

Luigi Marseglia, Luca Mascaretti, Elena Bevilacqua, Annamaria
Pasi, Miryam Martinetti, Carmine Tinelli

PII: S1568-9972(17)30257-4
DOI: doi:10.1016/j.autrev.2017.10.007
Reference: AUTREV 2074
To appear in:
Received date: 14 August 2017
Accepted date: 20 August 2017

Please cite this article as: Annalisa De Silvestri, Cristina Capittini, Dimitri Poddighe, Gian
Luigi Marseglia, Luca Mascaretti, Elena Bevilacqua, Annamaria Pasi, Miryam Martinetti,
Carmine Tinelli , HLA-DRB1 alleles and juvenile idiopathic arthritis: Diagnostic clues
emerging from a meta-analysis. The address for the corresponding author was captured
as affiliation for all authors. Please check if appropriate. Autrev(2017), doi:10.1016/
j.autrev.2017.10.007

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 ACCEPTED MANUSCRIPT
HLA-DRB1 alleles and Juvenile Idiopathic Arthritis: diagnostic clues emerging
from a meta-analysis.

Annalisa De Silvestri1, Cristina Capittini1, Dimitri Poddighe2*, Gian Luigi Marseglia2, Luca
Mascaretti3, Elena Bevilacqua3, Annamaria Pasi4, Miryam Martinetti4, Carmine Tinelli1

1
Servizio di Epidemiologia Clinica e Biometria, Direzione Scientifica, Fondazione IRCCS

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Policlinico San Matteo, Pavia
2
Università degli Studi di Pavia

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3
Laboratorio di Tipizzazione Tissutale, Dipartimento di Medicina Trasfusionale, Azienda Sanitaria
Universitaria Integrata di Trieste

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4
Laboratorio di Immunogenetica, Servizio di Immunoematologia e Trasfusione, Fondazione
IRCCS Policlinico San Matteo, Pavia
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*
corresponding author
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ABSTRACT
Juvenile Idiopathic Arthritis (JIA) is characterized with a variable pattern of articular involvement
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and systemic symptoms and, thus, it has been classified in several subtypes. Genetic predisposition
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to JIA is mainly due to HLA class II molecules (HLA-DRB1, HLA-DPB1), although HLA class I
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molecules and non-HLA genes have been implicated, too. Here, we carried out a meta-analysis on
selected studies designed to assess HLA genetic background of JIA patients, compared to healthy
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controls and, particularly, we focused our attention on HLA-DRB1. In summary, our meta-analysis
showed four main findings regarding HLA-DRB1 locus as a genetic factor of JIA: i) HLA-
DRB1*08 is a strong factor predisposing to JIA, both for oligo-articular and poly-articular forms
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(oJIA > pJIA); ii) HLA-DRB1*01 and HLA-DRB1*04 may be involved in the genetic
predisposition of Rheumatoid Factor (RF) positive forms of JIA; iii) HLA-DRB1*11 was
confirmed to be predisposing to oligo-articular JIA; iv) HLA-DRB1*04 was confirmed to have a
role in systemic JIA. Importantly, the positivity for the RF seems to select the JIA clinical subset
with the strongest immunogenetic similarities with the adult form of rheumatoid arthritis.

Keywords: Juvenile Idiopathic Arthritis; HLA-DRB1; JIA classification; meta-analysis.

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Abbreviations:
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- JIA: Juvenile Idiopathic Arthritis;
- RF: Rheumatoid Factor;
- ACR: American College of Rheumatology;
- EULAR: European League Against Rheumatism;
- ILAR: International League of Associations for Rheumatology;
- OR: Odds Ratio;
- HLA: Human Leukocyte Antigens.
- GWAS: Genome-Wide Association Studies.
- TNF: Tumor Necrosis Factor.

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- IL: Interleukin.
- PTPN22: Protein Tyrosine Phosphatase, Non-receptor, type 22;

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- MIF: Macrophage migration Inhibitory Factor.

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Disclosure: The authors declare no conflict of interests.

Funding: This research did not receive any specific grant from funding agencies in the public,
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commercial, or not-for-profit sectors.

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1. INTRODUCTION
Juvenile Idiopathic Arthritis (JIA) is defined as chronic arthritis persisting for more than 6 weeks in
children being younger than 16 years, without any identifiable etiology. It is the most common
chronic joint disease of childhood, as the annual incidence is 2-20 cases per 100,000 persons in
high-income countries [1].
JIA is characterized with a variable pattern of articular involvement and systemic symptoms may be
variably present, too. Indeed, in the 1970s, a committee of the American College of Rheumatology
(ACR) and the European League Against Rheumatism (EULAR) proposed different classifications

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of Juvenile Chronic Arthritis (JCA) and Juvenile Idiopathic Arthritis (JIA), respectively. In order to
eliminate inconsistencies between these two classifications, in the late 1990s the Task Force for

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Classification Criteria of the Pediatric Standing Committee of the International League of

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Associations for Rheumatology (ILAR) provided an internationally agreed system of definitions in
order to improve the clinical definition of JIA. [2-3]
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Currently, most paediatric rheumatologists agree that different subsets of JIA might represent
distinct diseases, as regards immune-pathological aspects. [1,4] Indeed, as most immune-mediated
diseases, JIA is a multi-factorial disease caused by currently undefined environmental agents
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overlapping a complex genetic background. There are substantial evidences for an important
genetic contribution to JIA and, in particular, HLA genes have been demonstrated to play a
fundamental role. [5]
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Genetic predisposition to JIA is mainly due to HLA class II molecules (HLA-DRB1, HLA-DPB1),
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although HLA class I molecules (HLA-A, HLA-B) resulted to be implicated, too. [6,7] Table I
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shows the main findings of studies investigating HLA association and JIA subtypes that have been
reported in literature so far. [8] However, several non-HLA genes (such as PTPN22, MIF, Il-6
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promoter, Il-10 promoter and TNF-α) emerged as additional genetic factors involved in JIA. [9].
Initial findings on HLA genetics in JIA derived from association and linkage studies and, currently,
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those have been confirmed by genome-wide association studies (GWAS). [10]

Here, we aimed at evaluating the interplay of specific HLA class II allelic groups/alleles in JIA, by
conducting a meta-analysis on selected studies designed to assess HLA genetic background of JIA
patients, compared to healthy controls.

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Table I - HLA genotype and JIA subtypes: main findings from the medical literature.

JIA subtype Predisposing HLA Protective HLA

allelic groups allelic groups

Systemic arthritis DRB1*04 (northern Europe) Not reported

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DRB1*08
Oligoarthritis DRB1*11

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DRB1*13 HLA-DRB1*04
DPB1*02 HLA-DRB1*07
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A*02 (Early onset)
B*27 (Late onset)
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Polyarthritis
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RF+ DRB1*04 Not reported

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DRB1*01
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RF- DPB1*03
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B*27 Not reported

Enthesitis-related arthritis DRB1*08
DPB1*03

Psoriatic arthritis DRB1*11 Not reported

DRB1*12

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2. MATERIALS AND METHODS

2.1 Protocol
We conceived a protocol including review questions, selection and eligibility criteria, primary and
secondary endpoints, search strategy, methods for data extraction, methods for assessing study

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quality and risk of bias, strategy for data synthesis, and statistical methodology. On 26 July 2017,
the protocol entitled “Association between HLA class I (A, B, and C) and class II (DRB1, DQA1,

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DQB1, DPA1, and DPB1) polymorphisms and Juvenile Rheumatoid Arthritis: a meta-analysis” was

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published in the PROSPERO International prospective register of systematic reviews and from that
date onwards it is available from http://www.crd.york.ac.uk/PROSPERO.
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2.2. Search strategy
We performed a systematic search of MEDLINE/PubMed, EMBASE, Web of Science, and
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Cochrane databases, retrieving all publications (case-control study, cross-sectional and retrospective
cohort study, or mixed design like nested case-control and cohort) on the association between HLA
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class II allelic groups and alleles and Juvenile Idiopathic Arthritis in infants and children (<18
years). We searched all English-written articles published in up to 28 February 2017. An expert
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librarian performed the search using the following MeSh terms: („„Juvenile Rheumatoid Arthritis)
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AND („„HLA‟‟ OR „„human leukocyte antigen‟‟) AND („„polymorphism‟‟ OR „„variant‟‟ OR

„„genotype‟‟ OR “allele”).
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Selection criteria were: HLA class II genes; any DQ and DR molecules; Juvenile Idiopathic
Arthritis. Two investigators independently performed data extraction according to the selection
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criteria. The third participant was consulted for discussion to reach agreement concerning
discrepancies. The following items were extracted from each study: first author‟s last name,
publication date, country of origin, numbers of cases and controls, typing method. Figure 1 shows
the complete flow diagram according to PRISMA statement. [11]

2.3 Risk of bias (quality) assessment

Following a quality assessment tool for genetic data [Quality Assessment of Genetic Studies in
Systematic Reviews (QUAGENS), [12] proposed by our multidisciplinary panel (statisticians,

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clinical epidemiologists, geneticists, clinicians, meta-analysts), three pairs of reviewers (one for the
clinical criteria, one for laboratory issues, one for methodology tools) working independently and
with adequate reliability verified the following aspects:
1. Clinical data: the presence of spectrum disease biases, the possible enrollment of incident or
prevalent cases, the inclusion of controls not selected from the same source population as the case-
subjects, the occurrence of differential participation in cases and controls.
2. Laboratory issues: the misclassification of genotypes or serotypes (including the types and
quality of samples, timing of collection, and the method used for HLA typing), the actual laboratory
staff blinded to outcome, the mention of quality controls.
3. Methodological features: the possible population stratification, the presence of multiple

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testing and pre-study odds of true finding (it would be useful to interpret the results in the context of
how many polymorphisms have been studied), the assessment of HW equilibrium in controls.

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Each question was answered as “yes”, “no” or “unclear”.

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2.4 Data extraction NU
After a critical reading of the articles, two investigators independently performed data extraction
according to the inclusion criteria listed above. The third participant was consulted for discussion to
reach agreement concerning discrepancies. The following items were extracted from each study:
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first author‟s last name, publication date, country of origin, numbers of cases and controls, typing
method. All the selected studies included in the present meta-analysis are summarized in Table II.
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2.5 Data synthesis and meta-analysis

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STATA and Meta-disc was used for statistical analysis to perform meta-analysis. Heterogeneity
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was checked by the Chi2 test and the I-squared statistic [13]. Statistical heterogeneity was defined
by a P value less than 0.10 for the Chi-squared test and an I-squared statistic greater than 50%.
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When there was no statistical evidence for heterogeneity in effect sizes, the fixed-effect model was
used [14] to meta-analyze ORs or RRs in probands; when significant heterogeneity was identified,
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the random-effects model was used [15] to explore sources of significant heterogeneity.

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Figure 1. Flow diagram according to PRISMA statement

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Table II –Main aspects of studies included in the meta-analysis.

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Reference
Publication
Clinical criteria
Number of
R I
Sub-types of JIA studied HLA genes
Year patients

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[16] 2003 JIA 268
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PAUCIARTICULAR-ONSET JIA (PERSISTENT
and EXTENDED), POLYARTICULAR ONSET JIA
(RF+)
HLA-B, DRB1,DPB1

[17] 2009 ILAR 31

M A PsA HLA-B, DRB1, DPB1

[18] 2002 ILAR

E D 314 JIA, AS, SEA, PsA, ARTHRITIS WITH IBD HLA-B, DRB1, DPB1

[19] 2004 JIA

P T 65
PAUCIARTICULAR, POLYARTICULAR RF+
HLA-DRB1,DQB1

[20] 1994
C
EULAR E 160
AND RF-, SYSTEMIC JIA

PAUCIARTICULAR EARLY ONSET JCA

HLA-DRB1,
DQB1,DQA1

[21] 2010
A C ILAR 820
POLYARTICULAR RF-, OLIGOARTICULAR JIA
(PERSISTENT AND EXTENDED)
A, B, C, DPA1, DPB1,
DQA1, DQB1. DRB1

NEW YORK MODIFIED

[22] 1995 63 JUVENILE ANCHYLOSING SPONDYLITIS B27+ HLA-B, DRB1, DPB1
CRITERIA

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OLIGOARTICULAR, POLYARTICULAR RF+

[23] 2010 ILAR 120 DQB1, DRB1
AND RF-, SYSTEMIC

[24] 2002 JIA 632

NEGATIVE
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PAUCIARTICULAR AND POLYARTICULAR RF
DQA1, DQB1, DRB1

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Legend: AS= ankylosing spondylitis; IBD= inflammatory bowel disease; JCA=Juvenile chronic arthritis; JIA= juvenile idiopathic arthritis; PsA=
R
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psoriatic arthritis; RF= rheumatoid factor; SEA = Seronegative entesopathy and arthropathy.

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3. RESULTS

3.1. Study selection and characteristics

Based upon the systematic search strategy reported in the Materials and Methods section, we
initially identified 565 articles, and after multiple rounds of selection following the exclusion
criteria listed in Figure 1, 27 articles were chosen for a full-text evaluation, of which 9 were

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included in the meta-analysis. Figure 1 shows the flowchart from the systematic search to the
choice of those articles fitting the inclusion criteria and thus answering to the meta-analytic question

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on quantifying the risk of carrying particular HLA-B and HLA class II (DRB1, DPB1) allelic

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groups being predisposed to develop JIA. Consequently, we evaluated the strength of the
association between HLA allelic groups and alleles and the susceptibility to JIA, and we analyzed
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the appropriateness of HLA testing in JIA diagnosis in probands.
Overall, the 9 studies included 2473 JIA patients and 9543 healthy controls. Selected characteristics
of the 9 included studies are summarized in Table II. Seven studies included Caucasian populations
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(chiefly from North Europe) and two studies included Mexican and Colombian mestizo populations
(from Latin America). Due to the limited number of ethnical groups, we could not conduct an
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ethnicity-specific meta-analysis.
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3.2. Quality of studies

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The quality of studies in terms of laboratory method description, statistical methodology and
clinical features was mainly low. The majority of studies did not explain at all or were not clear for
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the majority of items (Figure 2).

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3.3. Meta-analysis: association among JIA susceptibility and HLA-B, HLA-DRB1 and HLA-
DPB1 alleles.
Among the 9 articles selected for the meta-analysis, two studies reported the frequency of the HLA-
B*27, three studies analyzed the allelic group frequencies of HLA-DQA1, HLA-DQB1 and HLA-
DPB1 genes, four studies analyzed the allele frequency of the HLA-DPB1 gene, whereas all the 9
articles reported the allele frequency of the HLA-DRB1 gene (Table III).
The results of the meta-analyses carried out for each locus to verify the correlation between specific
allelic groups or alleles and susceptibility to JIA are reported in Table III. We performed meta-

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analysis with at least two studies reporting allelic group or allele frequency: thus some allelic
groups of the HLA-DRB1, HLA-DQA1, HLA-DQB1 and HLA-DPB1 genes were not considered
as reported only once.
Three allelic groups significantly conferred an increased risk for JIA: HLA-B*27 (OR: 2.635, IC:
1.943 - 3.574), HLA-DRB1*08 (OR: 6.264; IC: 5.045 - 7.778) and HLA-DRB1*11 (OR: 1.810; IC:
1.222 - 2.679). On the contrary, HLA-DRB1*04 showed a significantly protective role for JIA (OR:

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0.648; IC: 0.391 - 1.075) (Table III).
The Egger‟s regression test showed no evidence of publication bias (Egger‟s regression test p-

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values > 0.1).

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SI NO non chiaro
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0% 25% 50% 75% 100%

Are the statistical methods clearly described?
Are the statistical methods used to control for confounding clearly described?
Are software version used and options (or settings) chosen appropriated?
Are the methods used to examine subgroups and interactions appropriate?
Do authors explain how missing data were addressed?
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In cohort study, do authors explain how loss to follow-up was addressed?

In case-control study, do authors explain how matching of cases and controls was…
In cross-sectional study, do authors describe analytical methods taking account of…
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Do authors describe any sensitivity analyses?

Was Hardy–Weinberg equilibrium considered and, if so, how?
Were methods for inferring genotypes or haplotypes clearly defined?
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Were methods used to assess or address population stratification clearly defined?

Were methods used to address multiple comparisons or to control risk of false positive…
Were methods used to address and correct for relatedness among subjects clearly…
Is the source of biological samples clearly defined?
Is the method of DNA extraction clearly defined?
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Are genotyping methods and platforms clearly defined?

Do authors describe the use of algorithm to assign allele/genotype data?
Did the study describe previous testing?
Do authors clearly define where the analyses the testing has been carried out (laboratory…
If there is more than one group, are laboratory methods comparable?
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Are genotypes assigned using all of the data from the study simultaneously or in smaller…
Do authors describe any error rates?
Do authors explain how they managed the lost data?
Is the methods of patient selection clearly described in terms of clinical eligibility criteria?
Is the methods of patient selection clearly described in terms of sources of selection…
Did the study avoid inappropriate exclusions of patients?
Was a consecutive or random sample of patient enrolled?
Could the selection of patients have introduced bias?
Is there concern that the included patients do not match the meta-analytic question?
Is the methods of control selection clearly described?

Figure 2. Quality of studies as concerns description of laboratory methods, statistical methodology

and clinical features.

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N of
HLA allelic
group/allele
included Patients Healthy Controls OR IC 95% P-value Z

P TModel
Het P-
value
I2 value
for Het

B*27
studies
2 170/649 70/590 2.635 1.943 - 3.574 < 0.001
R I
6.23 F 0.898 0
DRB1*01
DRB1*04
7
7
428/1997
427/1997
1197/6050
2162/6050
1.127
0.648
0.945 - 1.346
0.391 - 1.075
S C
0.184
0.093
1.33
1.68
F
R
0.607
< 0.001
0
88.8
DRB1*08
DRB1*11
7
7
564/1983
501/1997
511/6147
726/6050
6.264
1.810
5.045 - 7.778

N
1.222 - 2.679 U < 0.001
0.003
16.61
2.96
F
R
0.095
0.001
44.4
73.1
DRB1*13
DRB1*16
DPB1*01:02
5
4
3
307/1348
48/1108
78/226
274/5460
1360/5262
56/295
1.900
1.201
2.165 M A
0.809 - 4.463
0.469 - 3.075
1.738 - 2.697
0.141
0.703
< 0.001
1.47
0.38
6.90
R
R
F
< 0.001
0.011
0.964
91.7
73.1
0
DPB1*01:03 2 150/649 118/590

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1.202 0.916 - 1.578 0.185 1.33 F 0.943 0
Table III. Major findings of meta-analysis: association between HLA allelic groups and alleles and overall JIA susceptibility. OR: odds ratio; CI:

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confidence interval; F: fixed; R: random; Het: heterogeneity.

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3.4. Meta-analysis: association among susceptibility to specific subtypes of JIA and HLA-B,
HLA-DRB1 and HLA-DPB1 alleles.
The number of studies reporting HLA allelic group/allele frequencies and positivity for the
rheumatoid factor (RF) in different forms of JIA (oligoarthritis, polyarthritis, systemic arthritis) are
reported in Table IV. We performed a meta-analysis with at least two studies reporting allelic
group or allele frequency, thus HLA-B*27 and some allelic groups/alleles of the HLA-DRB1 and

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HLA-DPB1 genes were not considered.
As concerns oligoarthritis, four studies reported the frequency of DRB1*01, DRB1*04, DRB1*08

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and DRB1*11; three studies reported the frequency of DRB1*13; two studies reported the

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frequency of DRB1*16, DPB1*01:02 alleles. For Polyarthritis without positivity to RF, three
studies reported the frequency of DRB1*01, DRB1*04, DRB1*08, DRB1*11; two studies reported
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the frequency of DRB1*13 and of DPB1*01:03. For polyarthritis with positivity to RF, two studies
reported the frequency of DRB1*01, DRB1*04, DRB1*11. For systemic arthritis, two studies
reported the frequency of DRB1*01, DRB1*04, DRB1*11 alleles.
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Three allelic groups/alleles significantly conferred an increased risk for JIA oligoarthritis:
DRB1*08 (OR: 9.2, IC: 6.7-13), DRB1*11 (OR: 2.9, IC: 1.9-4.3), and DPB1*01:02 (OR: 4.4, IC:
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3.1-6.2). On the contrary, HLA-DRB1*04 showed a significantly protective role for JIA oligo-
arthritis (OR: 0.4; IC:0.2-0.8).
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Three allelic groups/alleles significantly conferred an increased risk for JIA polyarthritis without
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positive RF: DRB1*08 (OR: 6.0, IC: 4.0-8.9), DRB1*11 (OR: 1.8, IC: 1.2-2.5), and DPB1*01:03
(OR: 2.9, IC: 1.9-4.3) (Table IV). Two allelic groups significantly conferred an increased risk for
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JIA Polyarthritis with positive RF: DRB1*01 (OR: 2.5, IC: 1.1-5.9), and DRB1*04 (OR: 2.1, IC:
1.2 - 3.9).
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Only HLA-DRB1*04 significantly conferred an increased risk for systemic JIA (OR: 1.9; IC: 1.2-
3.0).

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Oligoarthritis Polyarthritis RF- Polyarthritis RF+ Systemic arthritis

2 2
HLA allele / N OR I N OR I N OR I2 N OR I2
allelic group (95%CI) (95%CI) (95%CI) (95%CI)

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B*27 1 1 1
DRB1*01 4 0.9 0% 3 0.9 62% 2 2.5 0 2 2.3 72%
(0.7-1.2) (0.4-2.1) (1.1-5.9) (0.6-8.0)

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DRB1*04 4 0.4 82% 3 1.0 80% 2 2.1 0 2 1.9 12%
(0.2-0.8) (0.5-2.1) (1.2 - 3.9) (1.2-3.0)
DRB1*08 4 9.2 0% 3 6.0 0% 1 1

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(6.7-13) (4.0-8.9)
DRB1*11 4 2.9 55% 3 1.8 35% 2 0.7 0 2 0.5 66%
(1.9-4.3) (1.2-2.5) (0.2-2.3) (0.1-3.9)
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DRB1*13 3 1.5 83% 2 1.1 0% 1 1
(0.7-3.3) (0.7-1.5)
DRB1*16 2 1.1 66% 1 0 0
(0.3-3.6)
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DPB1*01:02 2 4.4 0% 1 1 1
(3.1-6.2)
DPB1*01:03 1 2 2.9 0% 1 1
(1.9-4.3)
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Table IV. Association between HLA allelic groups/alleles and JIA subgroups. OR: odds ratio; CI:
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confidence interval.
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4. DISCUSSION
Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous disease, as seven categories have

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been currently defined, according to ILAR classification. The clinical presentation of JIA among
children is variable as regards several aspects (systemic symptoms, number and types of joints

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involvement, extra-articular disturbances, age of onset, temporal patterns of clinical manifestations,

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etc.). [1,3] Therefore, some genetic factors may provide important insights for understanding the
etiology and pathogenesis of different forms of JIA. As a consequence, a better knowledge of the
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genetic background JIA sub-groups may improve the current classification system and help the
clinicians to achieve a correct and early diagnosis.
Several studies showed that the major histocompatibility complex (MHC) on chromosome 6
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includes the most important genetic risk factor for JIA, but many of those have been limited by the
modest sample size. [10] Therefore, the epidemiological approach through meta-analysis could
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partially overcome such a limitation. Here, we reviewed and selected the studies analyzing HLA
genes in JIA, in order to provide a study population being large enough to evaluate the associations
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with class II HLA genes. Indeed, our meta-analysis included 2473 JIA patients and 9543 healthy
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pediatric controls.
A very recent study by Hinks A et al. described the fine mapping of MHC locus in JIA. These
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authors identified some category-specific associations for the most common forms of JIA. Probably,
their most striking result was that rheumatoid factor (RF)-negative poly-articular JIA and oligo-
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articular JIA shared genetic similarities in HLA-DRB1 locus and, in particular, at the amino acid
position 13, where the presence of glycine resulted to confer an OR ≥ 2. Moreover, a similar OR
was found between systemic JIA and HLA-DRB1*11. [25] On the contrary, our meta-analysis
provided different results in this regard. Indeed, although HLA-DRB1*11 showed an overall
association to JIA, in the sub-analysis for the main JIA categories, namely oligo-articular, poly-
articular and systemic, actually we found an OR ≥ 1 only in the first two subtypes.

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A recent comprehensive review on immunogenetics of JIA by Hersh AO and Prahalad S

summarized the current evidences regarding HLA and non-HLA susceptibility loci for specific
subtypes of JIA, including oligoarticular/polyarticular RF-negative JIA and systemic JIA. [10]
Importantly, these authors considered together RF-negative oligo-articular and poly-articular JIA, as
these two categories (accounting for ~70% of all JIA cases), resulted to be phenotypically similar
(e.g. sex ratio, age of onset, ANA positivity, risk of uveitis) with the exception of the number of

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affected joints. Several HLA-DRB1 alleles have been associated to oligo-articular and poly-
articular JIA, according the aforementioned systematic review; importantly, both subtypes shared

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HLA-DRB1*08 as a common predisposing factor. Our meta-analysis confirmed that carrying HLA-

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DRB1*08 is a strong factor predisposing to JIA (OR ≅ 6) and, actually, the most remarkable
association was with oligo-articular (OR = 9.2, 95% CI = 6.7-13) and poly-articular JIA (OR = 6,
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95% CI = 4.8-9) rather than with systemic JIA.
In addition, we analyzed RF- and RF+ poly-articular JIAs differentially and we found some
statistically significant results, as HLA-DRB1*01 and HLA-DRB1*04 resulted to be associated to
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RF+ forms only. Although an association between RF+ poly-articular JIA and HLA-DRB1*04 was
previously reported by Fernandez-Vina M several years ago. [26] Interestingly, HLA-DRB1*04 is
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the main allelic group associated with rheumatoid arthritis and it appears to be protective for the
development of most forms of JIA, as emerged also from our data.
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Other HLA-DRB1 allelic groups were reported to be associated to oligo-articular JIA, such as
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HLA-DRB1*11 and HLA-DRB1*13. [10,23,27] The present meta-analysis confirmed an increased

susceptibility to both oligo-articular (OR = 2.9) and poly-articular JIA (OR = 1.8) in children
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carrying HLA-DRB1*11, but in a lesser extent than HLA-DRB1*08 carriers, who actually have not
resulted to be prone to develop systemic JIA. No statistically significant association was confirmed
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for HLA-DRB1*13. Actually, these allelic groups have been recently proposed to play a role in the
predisposition of ocular complications in JIA children rather than in the onset of arthritis. Indeed,
Angeles-Han ST et al. carried out a high-resolution HLA-DRB1 genotyping in a cohort of 107
children with oligo-articular and poly-articular RF-negative JIA and 373 non-Hispanic white
healthy children: compared to controls and children with JIA alone, those patients with JIA-
associated uveitis showed an increased odds of carriage of HLA-DRB1*11 (OR = 9) and *13 (OR =

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8.6). [28] However, the articles included in the present meta-analysis provided no enough data to
allow this specific evaluation concerning HLA-DRB1 and the risk of uveitis in JIA patients.
As regards systemic JIA (sJIA), based upon the available data for meta-analysis, the only
statistically significant association resulted to be with HLA-DRB1*04. Such a finding resulted to be
in agreement with the evidences emerging from the systematic review by Hersh AO and Prahalad S.
[10] Here, a strong association with HLA-DRB1*01 in a study involving Mexican population is

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reported, too. [23] Actually, our meta-analysis found a predisposing value of the OR (=2.3) related
to HLA-DRB1*01, but such a result reached no statistical significance. Therefore, it is likely that

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HLA-DRB1*01 may predispose to systemic JIA, but the variable associations might be affected by

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the ethnicity. Recently, Ombrello MJ et al. performed an association study including 982 children
with sJIA and 8,010 healthy control subjects from nine countries. Importantly, they provides strong
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evidence for a role for HLA-DRB1*11 as a major risk factor for sJIA (OR 2.3). [29] However, as
we mentioned previously, our data did not support this conclusion, but the number of studies
included our meta-analysis that was suitable for this specific investigation was limited.
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5. DISCUSSION
In conclusion, our meta-analysis showed four main findings regarding HLA-DRB1 locus as a
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genetic factor of JIA: i) HLA-DRB1*08 is a strong factor predisposing to JIA, both for oligo-
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articular and poly-articular forms (oJIA > pJIA); ii) HLA-DRB1*01 and HLA-DRB1*04 may be
involved in the genetic predisposition of RF+ forms of JIA; iii) HLA-DRB1*11 was confirmed to
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be predisposing to oligo-articular JIA; iv) HLA-DRB1*04 was confirmed to have a role in systemic
JIA. The positivity for the Rheumatoid Factor seems to select the JIA clinical subset with the
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strongest immunogenetic similarities with the adult form of rheumatoid arthritis characterized by
the arthritogenic HLA-DRB1 shared epitope.

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HIGHLIGHTS:

- HLA-DRB1*08 is a strong factor predisposing to oligo- and poly-articular JIA.

- HLA-DRB1*01 and HLA-DRB1*04 may be involved in the genetics RF+ JIA.
- HLA-DRB1*11 was confirmed to be predisposing to oligo-articular JIA.
- HLA-DRB1*04 was confirmed to have a role in systemic JIA.

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- RF positivity seems to select JIA subset being immune-genetically similar to RA.

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