Jittawattanarat et al. BMC Pediatrics(2024) 24:555
https://doi.org/10.1186/s12887-024-05032-2

BMC Pediatrics

RESEARCH

Open Access

Prevalence of HLA-B27, clinical characteristics
and treatment outcomes in children
with enthesitis-related arthritis
Boonsiri Jittawattanarat1, Sirirat Charuvanij2, Sirikarn Tangcheewinsirikul3 and Maynart Sukharomana2*
Abstract
Background Enthesitis-related arthritis (ERA) is a subtype of juvenile idiopathic arthritis with high disease burden.
The objectives of this study were to explore the prevalence of HLA-B27, clinical characteristics, and treatment
outcomes in children with ERA and compare the differences between HLA-B27 positive and negative patients.
Methods A retrospective cohort study at a pediatric rheumatology clinic in a tertiary referral hospital in Bangkok,
Thailand, including ERA patients with at least 6 months of follow-up (July 2011-April 2022) was performed. Data
were collected from medical records from diagnosis to recent follow-up, assessing disease activity and treatment
outcomes, with an analysis comparing HLA-B27 positive and negative patients. Descriptive statistics were used fordata analysis.
Results There were 59 ERA patients with mean age ± SD at diagnosis 11.2 ± 2.5 years, 53 males (89.8%), and positive
HLA-B27 in 38 patients (64.4%). The HLA-B27 positive group had significantly higher levels of inflammatory markers atinitial diagnosis (p = 0.001), lower baseline hemoglobin (p = 0.001) and hematocrit (p = 0.002), higher disease activity
assessed by the Juvenile Spondyloarthritis Disease Activity score at 6 and 12 months of follow-up (p = 0.028 and 0.040,
respectively), increased utilization of bridging systemic corticosteroids (60.5% vs. 14.3%, p = 0.001) and anti-TNF (39.5%
vs. 9.5%, p = 0.018), and longer duration of methotrexate (median[IQR] 1.7[1.1–3.1] vs. 1.3[0.6–1.9] years, p = 0.040). The
HLA-B27 negative group had more prevalent hip arthritis than the positive group at initial diagnosis (66.7% vs. 28.9%,
p = 0.005) and during the course of the disease (71.4% vs. 36.8%, p = 0.011).
Conclusion Most of the ERA patients tested positive for HLA-B27. Throughout the follow-up period, thesepatients demonstrated greater disease activity, greater use of corticosteroids and anti-TNF, and longer duration of
methotrexate to control the disease.
Key points• HLA-B27 was tested positive in nearly two-thirds of enthesitis-related arthritis (ERA) patients.
• ERA patients with positive HLA-B27 had significantly higher levels of inflammatory markers with lower
hemoglobin and hematocrit at initial diagnosis, increased disease activity assessed by the Juvenile Spondyloarthritis*Correspondence:
Maynart Sukharomana
maynart.suk@mahidol.ac.th
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use,sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

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Disease Activity (JSpADA) score at 6 and 12 months of follow-up, greater utilization of bridging systemic
corticosteroids and anti-TNF, and longer duration of methotrexate use.
• ERA patients with negative HLA-B27 had more prevalent hip arthritis at initial diagnosis and during disease course.
• Application of the Assessment of SpondyloArthritis international Society (ASAS) classification for adultspondyloarthritis in ERA patients who entered adulthood showed the predominance of peripheral spondyloarthritis
in more than half of the patients.
Keywords Enthesitis-related arthritis, HLA-B27, Clinical characteristics, JSpADA score, Treatment outcomesIntroduction
Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in children, with anincident rate of 1.6–42.5/100,000 and a prevalence of 3.8–400/100,000 population [1, 2]. Enthesitis-related arthritis(ERA), one of the 7 subtypes classified according to theInternational League of Associations for Rheumatology(ILAR), can be classified by having arthritis and enthesitis
or arthritis/enthesitis along with at least 2 of the following: sacroiliitis or inflammatory back pain, positive blood
test for human leukocyte antigen (HLA)-B27, arthritis inmales with onset age greater than 6 years, symptomatic
anterior uveitis, and/or first-degree relative family historyof HLA-B27-associated disease [1]. The incidence of ERA
in Europe and the Middle East ranges from 5 to 15% of
all cases of JIA in children [3, 4]. In Thailand, previous
studies reported that ERA accounts for 21.5–33.7% of JIA
patients [5–7]. Due to the chronicity of the disease associated with severe arthritis and enthesitis, the treatment
of ERA has been more challenging than other subtypes
of JIA subtypes [8, 9]. Less than 20% of patients with ERA
would have inactive disease after 5 years of continuous
treatment, and some may develop ankylosing spondylitis
in 10 years, affecting morbidity and negatively affecting
quality of life [7, 10–12]. Accordingly, early diagnosis andprompt intervention can enhance long-term treatment
outcomes [7].
The treatment recommendation for ERA varies
based on disease severity, including non-steroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs, e.g. methotrexate andsulfasalazine), corticosteroids (intra-articular injection
as adjunctive therapy and oral prednisolone as bridging
therapy in moderate and high disease activity), and biologics e.g. antitumor necrosis factor (anti-TNF) for severe
and refractory patients having multiple active arthritis,
enthesitis and sacroiliitis that do not respond to othertreatment modalities [13]. In resource-limited countries,
biologics prescription is limited due to high costs [13],and Thailand is one of the countries that may not provide
it to all patients with refractory JIA because financial coverage depends on individual health benefit schemes andthe fulfillment of the eligibility criteria for biologics in
JIA, including refractory disease despite treatment withcombinations of NSAIDs, DMARDs and systemic corticosteroids [7].
From the literature review, HLA-B27 positivity is recognized as a poor prognostic factor. The incidence of positive HLA-B27 varies from 43 to 91.8% in ERA patients[14]. Patients with positive HLA-B27 tend to be lessresponsive to standard therapy and need more anti-TNF
to control the disease until remission [15–17]. Other
poor prognostic factors have been proposed in previous
studies, such as an age of onset of more than 8 years, hiparthritis, ankle arthritis within the first 6 months after
diagnosis, inflammatory back pain, and a family historyof ankylosing spondylitis [12, 17].
ERA encompasses diversity in clinical presentations,disease outcomes across different ethnicities, and country-specific access restrictions to biologics. Therefore, we
seek to look more closely at the aforementioned aspects
in relation to other global regions. The objectives of thisstudy were to explore the prevalence of HLA-B27, clinical characteristics, disease activity, and treatment resultsin children with enthesitis-related arthritis (ERA), and tocompare the differences between patients positive andnegative for HLA-B27. This study aims to provide useful information to refine treatment practices within the
country and globally.

Materials and methods
This retrospective cohort study was conducted at the
Department of Pediatrics, Faculty of Medicine Siriraj
Hospital, Mahidol University, a tertiary referral medical
center in Bangkok, Thailand. The data was acquired from
July 2011 to April 2022 through a retrospective review
of an electronic medical database recorded by pediatric rheumatologists. The study protocol was approvedby the Ethics Committee for Research in Humans of theSiriraj Institutional Review Board of the Faculty of Medicine Siriraj Hospital, Mahidol University (Certificate ofApproval number Si 359/2022). Due to the retrospective study design, the informed consent and assent were
waived by the Siriraj Institutional Review Board.
Participants in this study were patients diagnosed
with ERA according to ILAR classification criteria [1]with a minimum of 6 months of follow-up in the pediatric rheumatology clinic at Siriraj Hospital. In this study,

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

we reviewed and collected data from medical records offollow-up visits by pediatric rheumatologists to assess
clinical manifestations and disease activity during thetreatment course in ERA patients, with a comparison
between the HLA-B27 positive and negative groups.
Baseline patient characteristics included sex, age at onset
and diagnosis, family history of HLA-B27-related diseases
in first-degree relatives, recent infection history, and clinical manifestations (e.g. number of active arthritis, active
enthesitis, hip joint involvement, sacroiliitis, inflammatory back pain, limitation of joint range of motion, andacute symptomatic uveitis) were collected. Initial laboratory findings including complete blood count (CBC),erythrocyte sedimentation rate (ESR), C-reactive protein(CRP) and imaging studies were obtained. The HLA-B27
positivity was tested by using the microlymphocytotoxicity method [18]. We also documented individual patient
medication usage with duration, adhering to standard
recommendations for treatment of ERA [19, 20], consisting of NSAIDs, systemic corticosteroids, intra-articularcorticosteroids injections, methotrexate (subcutaneousor oral), sulfasalazine, and anti-TNF agents (etanercept,
adalimumab, or infliximab). In Thailand, the eligibility criteria for anti-TNF for JIA are considered based on
individual health benefit schemes and are indicated inpatients with refractory disease despite treatment withcombinations of NSAIDs, DMARDs, and systemic corticosteroids. Therefore, at our center, all ERA patients
received treatment combinations consisting of NSAIDs,
conventional DMARDs, and systemic corticosteroids as abridging therapy before addition of biological DMARDs.
To assess disease severity and monitor disease activity, the Juvenile Spondyloarthritis Disease Activity(JSpADA) score [19] was assessed at diagnosis, 6 months,
12 months, and at the most recent follow-up visit. The
JSpADA score consists of 8 items: active joint count,active enthesitis count, visual analog pain scale (VAS,
0–10), ESR or CRP, morning stiffness (greater than
15 min), clinical sacroiliitis, uveitis, and limited backmobility; these data were recorded in the medical records
during each visit by pediatric rheumatologists. Scores
range from 0 to 8, assuming equal importance for each
item, with higher scores indicating higher disease activity[19].
The status of the disease at the final follow-up was classified as active disease, inactive by clinical evaluation,
inactive by Wallace criteria, remission on medication andremission without medication [20]. Furthermore, refractory or relapsed disease was observed during the followup period [16]. The definitions of disease status in thisstudy were as follows:– 	 Inactive disease clinically was defined as the absenceof active arthritis or uveitis, with the physician’s

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global assessment of disease activity indicating that
there was no disease activity [20].
– 	 Inactive disease according to Wallace criteria was
met when the criteria for inactive disease was met byclinical measures and inflammatory markers (ESR or
CRP) were within the normal range [20].
– 	 Clinical remission was achieved when the inactive
disease criteria was met by the Wallace criteria.
This was further categorized into clinical remission
with medication (continuous inactivity while on
medication for at least 6 months) and clinicalremission without medication (continuous inactivity
for more than 12 months after discontinuing
medication) [21].
– 	 Refractory disease was defined as active arthritis
that persisted despite treatment with at least two
types of DMARDs for a minimum of 6 months or
the presence of active enthesitis or sacroiliitis despite
the use of at least one type of DMARD for at least 3
months [16].
– 	 Relapse in disease was defined as the reappearanceof active symptoms that did not meet the criteria forinactive disease after achieving clinical remission for
at least 6 months on or off medications.
– 	 Enthesitis was clinically diagnosed and defined as
inflammation of the enthesis (insertion of tendons,
ligaments and fascia), which can involve any site in
the body.
– 	 Sacroiliitis was clinically diagnosed and confirmed bymagnetic resonance imaging at diagnosis and during
the follow-up period.
In adults, the Assessment of SpondyloArthritis international Society (ASAS) classification criteria [22, 23] areused to assess spondyloarthritis (SpA), distinguishing
between the predominant peripheral and axial forms.
This study applied the ASAS classification to patientsolder than 16 years at their last visit.
All patients were clinically monitored during the follow-up period for the potential development of clinicalmanifestations for inflammatory bowel disease which
has been reported to be associated with juvenile spondyloarthropathy and HLA-B27 positivity [19]. In caseswith clinical index of suspicion for inflammatory bowel
disease, pediatric gastroenterology specialists were consulted for further evaluation including esophagogastroduodenoscopy with colonoscopy and serology tests.
Statistical analysis

The data collected were analyzed using IBM SPSS Statistics Version 28 (IBM Corp, Armonk, NY, USA). The
determination of the sample size was calculated by theprevious study conducted by Arkachaisri et al [14], by theformula n = Z2ɑ/2p(1-p)/e2 (defined type I error (α) = 0.05,

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

allowable error (e) = 0.1, Zɑ/2=Z0.025=1.96, p = 0.822) which
resulted in a calculated sample size of a minimum of 57.
Descriptive statistics were used for the analysis. Categorical data were conveyed as frequencies with percentages. Continuous data were presented as either
mean ± standard deviations (SD) for normally distributed
data or median with interquartile range (IQR) for nonnormally distributed data. Comparison of differences
between HLA-B27 positive and negative patients wasanalyzed using an independent samples t-test (for normally distributed data) and the Mann-Whitney U test (fornonnormally distributed data) for continuous variables,
while categorical variables were evaluated via the chisquare test and Fisher’s exact test. Statistical significancewas inferred for p-values less than 0.05. We adhered to
the reporting guidelines described in Strengthening theReporting of Observational Studies in Epidemiology [24].

Results
In a cohort of 62 patients diagnosed with ERA from a
total of 178 JIA patients who received care at the pediatric rheumatology outpatient clinic at Siriraj Hospital,
3 patients were excluded from the analysis due to a lackof sufficient follow-up duration of less than 6 months.

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Therefore, 59 patients were included in the analysis, all ofwhom had a follow-up duration of at least 6 months.
Baseline clinical characteristics at diagnosis

Most of the patients were males (53 of 59, 89.8%). Themean(± SD) duration of follow-up was 3.9 ± 2.4 years,
and the mean ± SD age of onset for patients in this study
was 10.8 ± 2.7 years. Positive HLA-B27 was found in 38
patients (64.4%). At diagnosis, a predominant proportion of patients presented with oligoarthritis, characterized by having an affected joint count ranging from 2
to 4 in 24 of 59 (40.7%) followed by polyarthritis, characterized by having an affected joint count of 5 or morein 23 of 59 (39.0%). Within the HLA-B27 positive group,
16 of 38 patients (42.1%) presented with oligoarthritis, while in the HLA-B27 negative group, polyarthritis
was more common in 9 of 21 patients (42.9%). Figure 1
shows a comprehensive overview of joint involvement
at diagnosis. Ankle joints were the most affected in 30
patients (50.8%), followed by hip joints in 25 patients(42.4%), knee joints in 24 patients (40.7%), and sacroiliitis
in 15 patients (25.4%). In the HLA-B27 positive group,
the most affected joints were ankle joints in 22 patients(58.9%), knee joints in 18 patients (47.4%), and hip joints

Fig. 1 Distributions of joint involvement at the time of diagnosis of enthesitis-related arthritis in HLA-B27 positive and negative patients (N = 59)

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

in 11 patients (28.9%). In contrast, the HLA-B27 negative
group had significantly higher percentage of hip involvement compared to the HLA-B27 positive group (14 of 21
patients, 66.7% vs. 11 of 38, 28.9%, p = 0.005).
Enthesitis was present in more than half of the patientsat diagnosis (59.3%, 35 of 59). The median number ofactive enthesitis (IQR) at the time of diagnosis was 1(0–3) site(s). The most common enthesitis site was the
Achilles tendon insertion into calcaneus in 27 patients(45.8%), and the other sites were quadriceps tendon topatella in 13 (22%); plantar fascia insertion into metatarsal head in 11 (18.6%), in calcaneus in 10 (16.9%),and base of metatarsal in 2 (3.4%); infrapatellar ligament
insertion to tibial tuberosity in 7 (11.9%) and patella in
3 (5.1%); hip extensor insertion into greater trochanterof femur in 3 (5.1%); common extensor insertion into
lateral epicondyle of humerus in 2 (3.4%); and supraspinatus insertion into greater tubercle of humerus
in 1 (1.7%). The HLA-B27 positive group had higher
percentage of enthesitis at diagnosis compared to the

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HLA-B27 negative group (68.4% vs. 42.9%), nearly significant (p = 0.056). There were significantly higher baseline inflammatory marker levels for both ESR and CRP in
the HLA-B27 positive group compared to the HLA-B27
negative group (p = 0.001). Regarding CBC, the HLA-B27
positive group also had significantly lower mean hemoglobin and hematocrit levels (p = 0.001 and p = 0.002,
respectively), and higher mean platelet count (nearlysignificant, p = 0.059). Table 1 summarizes the overall baseline clinical characteristics of ERA patients withcomparisons between the HLA-B27 positive and negative
groups.
Treatment and disease activity during the follow-up period

Regarding treatment, NSAIDs were the most commonlyprescribed drugs (96.6%, 57 out of 59), followed by methotrexate (84.7%, 50 out of 59). Significantly higher use ofbridging systemic corticosteroids (oral prednisolone) andanti-TNF were observed in the HLA-B27 positive groupcompared to the HLA-B27 negative group (p = 0.001 andTable 1 Baseline clinical characteristics of enthesitis-related arthritis patients comparing between HLA-B27 positive and negative
groupsVariables
Male, n (%)
Age at onset (years)
Age at diagnosis (years)
Duration of follow-up (years)
Family history of HLA-B27 related disease**, n (%)
Recent infection***, n (%)
Disease activity at diagnosis
Active joint count
Enthesitis, n (%)
Active enthesitis countHip arthritis, n (%)
Sacroiliitis, n (%)
Inflammatory back pain****, n (%)
Limited joint count
Acute symptomatic uveitis, n (%)
JSpADA score at diagnosis
Laboratory results at diagnosis
White blood cell count (cells/mm3)
Neutrophil (%)
Hemoglobin (g/dL)
Hematocrit (%)
Platelet (cells/mm3)
Erythrocyte sedimentation rate (mm/h)
C-reactive protein (mg/L)

Overall(N = 59)
53 (89.8)
10.8 ± 2.7
11.2 ± 2.5
3.9 ± 2.4
7 (11.9)
7 (11.9)

HLA-B27 positive(n = 38)35 (92.1)
10.9 ± 2.7
11.3 ± 2.6
4.3 ± 2.6
4 (10.5)
3 (7.9)HLA-B27 negative(n = 21)18 (85.7)
10.6 ± 2.6
11 ± 2.5
3.2 ± 23 (15.8)
4 (19.0)

p-value
0.656
0.618
0.729
0.112
0.568
0.233

2 (2–5)35 (59.3)
1 (0–3)25 (42.4)
14 (23.7)
11 (18.6)
1 (1–2)5 (8.5)3.5 (2.5–4.5)

2 (1.8-5)
26 (68.4)
1 (0–3)
11 (28.9)9 (23.7)
7 (18.4)
1 (1–2)4 (10.5)
4 (3-4.5)

3 (2–5)9 (42.9)
0 (0-2.5)
14 (66.7)
5 (23.8)
4 (19)
1 (1-2.5)
1 (4.8)3.25 (1.9–4.5)

0.438
0.056
0.154
0.005*
1.000
1.000
0.178
0.646
0.285

9867.8 ± 2630.3
57.4 ± 11.7
11.4 ± 1.7
36.0 ± 5.0
441118.6 ± 135312.8
41 (20–68)
19.7 (5.9–51)

10229.5 ± 2537.8
57.9 ± 10.3
10.9 ± 1.8
34.5 ± 5.1
465815.8 ± 145753.9
57 (32-73.5)
26.2 (13.3–67)

9213.3 ± 2729.5
56.4 ± 14.2
12.4 ± 1.2
38.6 ± 3.6396428.6 ± 102664.3
19 (7.35-55)
4.52 (0.65-22)

0.157
0.646
0.001*
0.002*
0.059
0.001*
0.001**p < 0.05**Family history of HLA-B27-related disease in first degree relatives including enthesitis-related arthritis, ankylosing spondylitis, inflammatory bowel disease withsacroiliitis, Reiter syndrome, and acute anterior uveitis***Recent infection referred to the history of recent infection prior to the onset of enthesitis-related arthritis****Inflammatory back pain referred to the history or the presence of inflammatory back pain
Abbreviations: JSpADA: Juvenile Spondyloarthritis Disease Activity

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

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0.018, respectively). There were also higher utilization of
methotrexate, sulfasalazine, and adjunctive intraarticularcorticosteroids in the HLA-B27 positive group, although
not statistically significant. Regarding the duration of the
medication, the use of sulfasalazine had the longest duration in both the HLA-B27 positive and negative groups.
Additionally, the duration of methotrexate use in the
HLA-B27 positive group was statistically significantly
longer, with a median duration (IQR) of 1.7 (1.1–3.1)
years (p = 0.04). The general treatment details and comparison between both groups are summarized in Table 2.
For clinical characteristics throughout the treatment
period, the appearance of hip arthritis from first diagnosis to the last visit was significantly higher in the negative HLA-B27 group compared to the positive HLA-B27
group (15 of 21, 71.4% vs. 14 of 38, 36.8%, p = 0.011).
The percentage of accumulated hip joint involvement
increased from baseline in both groups. There were also

higher percentage of patients with sacroiliitis, inflammatory back pain, and acute symptomatic uveitis in the
HLA-B27 positive group than in the HLA-B27 negative
group, without statistical significance. There were no
discernible differences in relapse and refractory disease
between the two groups classified according to HLAB27 status in the overall disease course. The details of
the clinical characteristics and disease course during thefollow-up period are shown in Table 2. No patients werediagnosed with inflammatory bowel disease during theclinical course.
In evaluating treatment outcomes using the JSpADA
score as a measure of disease severity, there were no differences in scores between the two groups at the time ofinitial diagnosis. However, a significant difference wasobserved in the HLA-B27 positive group compared to the
HLA-B27 negative group, revealing median (IQR) scoresof 1.75 (0.9-3) vs. 0.5 (0.5–1.7) at 6 months (p = 0.028) andTable 2 Overview of treatment and disease activity during the follow-up period
Variables
Treatment medications
NSAIDS, n (%)
Systemic corticosteroids, n (%)
Intraarticular corticosteroid injection, n (%)
Methotraxate, n (%)
Sulfasalazine, n (%)
Biological agents (anti-TNF), n (%)
Duration of medications use (years)
NSAIDs use
Prednisolone use
Methotrexate use
Sulfasalazine use
Biological agents (anti-TNF) use
On medication at last visit, n (%)
Clinical manifestation throughout the follow-up period
Acute symptomatic anterior uveitis, n (%)
Accumulative hip arthritis, n (%)
Accumulative sacroiliitis
Inflammatory back pain, n (%)
Accumulative active joint count, median (IQR)
Accumulative active enthesitis count, median (IQR)
Duration from diagnosis to onset of sacroiliitis (years)
Duration from diagnosis to hip arthritis (years)
Disease activity
Relapse disease, n (%)
Refractory disease, n (%)
Active disease at last visit, n (%)
JSpADA score at each time point
At 6 months of follow-up
At 12 months of follow-up
At last visit

Overall(N = 59)

HLA-B27 positive(n = 38)

HLA-B27 negative(n = 21)

p-value

57 (96.6)
26 (44.1)
18 (30.5)
50 (84.7)
37 (62.7)
17 (28.8)

36 (94.7)
23 (60.5)
14 (36.8)
35 (92.1)
28 (73.7)
15 (39.5)

21 (100)
3 (14.3)
4 (19.0)
15 (71.4)
9 (42.9)2 (9.5)0.285
0.001*
0.160
0.057
0.109
0.018*

1.4 (0.7–3.9)
1.0 (0.7–1.8)
1.6 (0.9–2.7)
2.4 (1.4–4.1)
1.2 (0.7-2.0)
41 (69.5)

1.5 (0.7–4.2)
1.0 (0.6–2.9)
1.7 (1.1–3.1)
2.8 (1.3–3.6)
1.6 (0.7-2.0)
29 (76.3)

1.3 (0.7–2.8)
1.3 (0.9–1.7)
1.3 (0.6–1.9)
1.9 (1.8–2.1)
1.3 (0.9–1.7)
12 (57.1)

0.704
0.356
0.040*
0.777
0.840
0.126

5 (8.5)29 (49.2)
23 (39)19 (32.2)
4 (2.0–7.0)
2 (0.8-4.0)
0 (0-0.6)
0 (0–0)4 (10.5)
14 (36.8)
15 (39.5)
13 (34.2)
3 (2–6)
2 (1-3.5)
0 (0-3.1)
0 (0-0.1)

1 (4.8)15 (71.4)
8 (38.1)
6 (28.6)
4 (2-7.5)
1 (0-4.5)
0 (0–0)0 (0–0)0.646
0.011*
0.917
0.657
0.684
0.516
0.205
0.164

13 (22)21 (35.6)
9 (15.3)

11 (28.9)
16 (42.1)
5 (13.2)2 (9.5)5 (23.8)
4 (19)

0.109
0.160
0.708

1.5 (0.5–2.5)
0.5 (0-1.5)
0 (0–1)1.75 (0.9-3)
1 (0.4-2)
0 (0-0.5)

0.5 (0.5–1.7)
0.5 (0-0.8)
0 (0-0.6)

0.028*
0.040*
0.768*p < 0.05
Abbreviations: anti-TNF: anti-tumor necrosis factor; NSAIDs: nonsteroidal anti-inflammatory drugs; JSpADA: Juvenile Spondyloarthritis Disease Activity

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

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Fig. 2 Trends in median scores for Juvenile Spondyloarthritis Disease Activity (JSpADA) assessed at 0, 6, 12 months, and the last visit in patients with HLAB27 positive and negative enthesitis-related arthritis

Fig. 3 Disease status at the last visit in HLA-B27 patients with positive and negative enthesitis-related arthritis (N = 59)

1 (0.4-2) vs. 0.5 (0-0.8) at 12 months (p = 0.04), as shownin Table 2. The trend is depicted in Fig. 2, illustrating an
overall downward trend in the median JSpADA scores inboth groups from diagnosis to the last visit. In particular, in the HLA-B27 negative group, the JSpADA scoresdemonstrated a reduction of more than 80% from diagnosis to 6 and 12 months of follow-up. At the same time,the HLA-B27 positive group showed a reduction of 50%
at 6 months and a reduction of 75% at 12 months fromthe time of diagnosis. However, both groups reached a
median JSpADA score of zero at their last visit.
At the last visit, among HLA-B27 positive patients, themajority achieved remission on medication, accounting for 37% (14 of 38 patients), while among HLA-B27
negative patients, the majority achieved remission without medication, representing 33% (7 of 21 patients). Figure 3 elaborates the disease status of patients with ERA
at the last visit by comparing the positive and negative

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

HLA-B27 groups, shown as percentage within eachgroup.
The ASAS classification criteria were applied to ERA
patients older than 16 years at the last visit, which
included a total of 23 patients. Of this, 13 of 23 (56.5%)
met the criteria for peripheral spondyloarthritis (SpA)
and 10 of 23 (43.5%) met the criteria for axial SpA.
Among those who met the peripheral SpA criteria, 10
of 13 patients had positive HLA-B27 as one of the SpA
characteristics. For those who met the axial SpA criteria,
9 of 10 patients had positive HLA-B27.

Discussion
Our study explored demographic data, clinical characteristics at baseline and disease course, treatment, disease activity, and outcomes in ERA patients. HLA-B27
positive patients (64.4%) had significantly higher levels
of inflammatory markers, lower hemoglobin and hematocrit at diagnosis, greater use of bridging systemic corticosteroids and anti-TNF, longer duration of methotrexate
use, and higher JSpADA scores at 6 and 12 months oftreatment. On the contrary, HLA-B27 negative patients
had significantly more hip arthritis at both baseline andduring the disease course.
The prevalence of HLA-B27 in our ERA patients was
64.4%, consistent with studies from another tertiary
center in Thailand, Singapore, China, Sweden, and theUnited States (US), where more than 50% of the patientswere HLA-B27 positive [14–16, 25–27]. On the contrary,a study from France reported HLA-B27 positivity lessthan 50% [28], while a study from Taiwan documented
positivity up to 97% [29]. This indicates potential ethnic variability as a contributing factor to the differencesin HLA-B27 positivity [14–16, 25–30]. The percentage of family history in first-degree relatives with HLAB27-related disease in our study (11.9%) was consistent
with previous studies ranging from 11-15.4% [14, 26,29]. However, higher prevalences of family history werereported in France (28%) [28] and China (27.4%) [25], in
contrast to the aforementioned studies.
In our study, most of the patients were males (89.8%),
with a mean age at the time of onset of 10.8 ± 2.7 years.
Comparisons with previous cohort studies revealed similar median onset ages ranging from 9.5 to 11.6 years [14,16, 25, 26, 29]. However, a previous study reported a later
median age onset of 14 years [28]. Most of the patientsat diagnosis presented with oligoarthritis (40.7%), alignedwith the findings of previous cohorts [14, 16, 26, 29].
The distribution of the joint at diagnosis predominantly
involved peripheral joints in the lower extremities, withthe most affected joint in our study being the ankle(50.8%), followed by the hip joint (42.4%) and the knee
joint (40.7%), in which these joints also emerged as the
top three affected joints in previous studies, although inPage 8 of 12

a different order; in the Singapore study, the hip joint was
the most common (43.8%), followed by the knee (37.7%)
and the ankle joint (26%); in another tertiary center inThailand, France and the US, the knee was the most common [14, 16, 26, 28].
When comparing two groups based on HLA-B27 status, our study reveals significantly higher inflammatory
markers (ESR, CRP), with lower hemoglobin and hematocrit at diagnosis in the HLA-B27 positive group. The
results of a previous multicenter study in the US showed
more inflammation occurring in the HLA-B27 positive
group compared to the negative group [26]. Interestingly,
a study from China which classified ERA patients into
those with and without fever reported that ERA patientswith fever showed more active disease at the beginningwith more anemia and thrombocytosis [24]. The trendsof anemia and thrombocytosis in the HLA-B27 positive
group could be explained by anemia of inflammation andreactive thrombocytosis. Therefore, these findings fromour study indicate more inflammation in the HLA-B27
positive group compared to the negative group, which
was consistent with previous studies [25, 26]. At diagnosis, our study identified slightly higher frequencies ofenthesitis, inflammatory back pain, acute symptomatic
uveitis and the JSpADA score at diagnosis, as well as
higher frequencies of sacroiliitis, inflammatory back pain,
and acute symptomatic uveitis during follow-up in the
HLA-B27 positive group, although without statistical significance, possibly due to the limited number of participants. A larger multicenter study in the US demonstrated
a significant increase in active joint counts, sacroiliitis,
and the JSpADA score at diagnosis among the HLA-B27
positive group [25]. Additionally, a study from Singapore
showed significantly higher incidences of sacroiliitis at
diagnosis and the course of treatment in the HLA-B27
positive group, also having higher incidences of uveitis,
active joint count, and enthesitis in the HLA-B27 positive group, although without statistical significance [14].
Therefore, our results emphasize a potential trend towardhigher disease activity and presence of associated findings such as sacroiliitis and uveitis in the HLA-B27 positive group compared to the HLA-B27 negative group.
In addition to HLA-B27 positivity, individuals withhip arthritis and sacroiliitis had been recognized to havepoor prognostic factors [15, 31]. Our data surprisingly
revealed a significantly higher incidence of hip arthritis
both at diagnosis and throughout the course of treatmentin the negative group for HLA-B27. Similarly, Singapore’s
findings showed a slightly higher number of hip arthritis
occurrences in the HLA-B27 negative group compared to
the HLA-B27 positive group at diagnosis (50% vs. 42.5%)
and during the follow-up period (69.2% vs. 58.3%) for thenegative and positive groups of HLA-B27, respectively,
although without statistical significance [14]. In contrast,

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

findings from another tertiary center in Thailand showedthat HLA-B27 positive patients had more hip involvement than HLA-B27 negative patients (46% vs. 18.8%)[16]. However, considering the occurrence of hip arthritis, particular attention should be paid to the observationof hip arthritis even in the negative HLA-B27 group forearly detection and proper treatment.
According to standard treatment recommendations, NSAIDs are considered the primary treatment of
DMARD, and systemic corticosteroids can be consideredas bridging therapy [13]. Our study showed that NSAIDs
were the most utilized drugs, followed by methotrexate, sulfasalazine, and prednisolone. While anti-TNF is
recommended for sacroiliitis [13], resource limitations,particularly limited access and high cost of biologic drugs[13], lead to alternative combinations of DMARDs and
NSAIDs in some countries [7, 31, 32], including Thailand[7, 32]. In Thailand, the eligibility criteria for anti-TNF
for JIA are considered based on individual health benefit schemes and are indicated in patients with refractorydisease despite treatment with combinations of NSAIDs,DMARDs, and systemic corticosteroids [7]. In our study,
28.8% of ERA patients met the indication for anti-TNF,
and HLA-B27 positive individuals were significantly
more likely to be prescribed it compared to HLA-B27
negative groups. This trend also existed for systemic corticosteroids as a bridging therapy for patients with higher
disease activity, which was significantly higher in HLAB27 positive individuals compared to HLA-B27 negative
groups. It should be noted that the duration of systemic
corticosteroids used in our study was longer than thestandard recommendations [20], to help control the disease in the early treatment phase, mainly for patients who
may need biologics but had limited access due to financial
problems or did not meet the indicated criteria according to the health benefit schemes. However, we acknowledge that the use of systemic corticosteroids may leadto disease damage as it is the predictor of extraarticulardamage [7] and is associated with a suboptimal quality oflife in JIA [5]. Furthermore, previous studies found a significantly higher incidence of anti-TNF use in HLA-B27
positive individuals compared to negative groups [14].
Our study also showed that the duration of methotrexate
was significantly longer in the HLA-B27 positive group,
possibly due to the higher disease activity that requireda prolonged period of medication to achieve disease control until remission.
Disease activity, monitored by the JSpADA score, did
not show significant differences at diagnosis, but wassignificantly higher in the HLA-B27 positive group at
6 and 12 months of follow-up. In the HLA-B27 negative group, the improvement in the JSpADA score wasgreater than in the HLA-B27 positive group, leading toa median score of 0 at the last visit in both groups. This

Page 9 of 12

was consistent with the study by Vilaiyuk et al. [6], which
demonstrated that HLA-B27 negative patients showed
more improvement than those with HLA-B27 positivein the first 3 months of the follow-up period, potentiallyindicating that the HLA-B27 positive group had a morerefractory course of the disease. Our study also showed ahigher proportion of refractory disease in HLA-B27 positive patients, although without statistical significance. At
the last visit in our study, active disease was observed in
15.3% and HLA-B27 positivity did not significantly affectthe outcome at the last visit, similar to the study by Arkachaisri et al. [14]. This could be attributed to HLA-B27
positive patients, despite having a higher disease activity score, receiving more systemic corticosteroids andanti-TNF compared to the HLA-B27 negative group.
Consequently, the disease outcome at the last visit did
not differ between the two groups. Among patients with
ERA who turned to adulthood, the application of ASAS
criteria showed the prevalence of peripheral SpA in morethan half of the patients, highlighting that patients with
the SpA spectrum who developed clinical manifestations earlier from childhood exhibit more peripheral
joint involvement. Additionally, younger age of onset
was associated with HLA-B27 positivity in Thai adults
with axial SpA [18]. Table 3 summarizes the cohorts ofpatients with ERA from various countries with comparisons with the present study [14, 16, 25–31, 33, 34]. The
results of our study add new information to the previous Thai cohort by highlighting the differences between
HLA-B27 positive and negative ERA patients in the
aspects of clinical characteristics at diagnosis and followup, disease activity, medications, and outcome, providing
data specifically for both groups and overall patients, aswell as the application of ASAS classification criteria inpatients who turned into adults with ERA to identify thedistinct phenotype, which can provide useful information
for adult rheumatologists during transition and longterm follow-up.
Although our study did not have any patients whodeveloped inflammatory bowel disease during the followup period, this potential association should be concernedin patients with ERA or juvenile spondyloarthropathy
especially those with positive HLA-B27 [19]. As mentioned earlier that ERA patients with positive HLA-B27
were more anemic and had higher inflammatory markers
at baseline, this group of patients may need close monitoring for development of possible inflammatory bowel
disease and require further work-up. For clinical implications, we propose that in ERA patients with positive
HLA-B27, those exhibiting higher inflammatory markers
at baseline may need further work-up for possible inflammatory bowel disease. Moreover, in ERA patients withpositive HLA-B27, routine magnetic resonance imaging
should be performed for early detection of active disease

Hong Kong

2023

2022
2021

2021
2019
2018
2018
2017
2015
2015
2011

Vilaiyuk [16]Naveen [31]Arkacharisri [14]Shih [29]Zanwar [27]Goirand [28]Gmuca [26]
Guo [25]
Srivastava [34]Demirkaya [33]

146
73
127
114
234
146
107
120

66
73

41

59

N

30.8
39.9
NA
NA
NA
NA
NA
18.9

NA
NA

40

33.1

11.9(9.4–14.0)
11 ± 3.2
14.3 ± 2.4 b
9.6(2.7)
11.6(9.8–13.7)a10.3a12(4–16)
15.3 ± 2.8b

39.7
16
43
29
55.6
43.8
21
NA

18.6
59

78

12(10.3–15)a10.2 ± 3.1
14(11–15)

23.7

Sacroiliitis(%)

10.8 ± 2.7

Age at onset(years)*Abbreviations: ERA: enthesitis-related arthritis; JIA: juvenile idiopathic arthritis; NA: not applicable

Age at enrollment

Age at diagnosis

b

a

82
97
86.5
43
59.2
58.9
79
63.3

75.8
98

95

64.4

%
Positiveof total HLA-B27
JIA(%)*Displayed as mean ± standard deviation or median (interquartile range)

Singapore
TaiwanIndia
France
USA
China
India
TurkeyThailandIndia

Thailand2024

Jittawattanarat(present study)
Chan [30]CountryYear

AuthorTable 3 Summary of ERA cohorts from various countries with comparison to the present study

24
97
NA
72
75.2
37
59
NA

43.9
90

NA

59.3

3.4
10
NA
NA
5.6
7.5
12
6.7

3
1.78

NA

8.5

43.8
NA
12.5
NA
19.2
35.6
NA
NA

40.9
31.5

34.1

42.4
Sacroiliitis(78)
Knee (62.1)
Sacroiliitis(59)
Hip (43.8)
NA
NA
Knee (58)Knee (45.7)
Knee (45.2)
NANA

Ankle (50.8)

Enthesi- Uveitis Hip
Most
tis (%)(%)
arthritis affected(%)
joint (%)

52.1
53
NA
NA
14.6
NA
NA
NA

NA
NA

NA

Systemiccorticosteroids
(%)
44.1

78.8
62
3.9
NA
NA
NA
NA
100

78.8
NA

NA

62.7

Sulfasalazine
(%)

77.4
74
15.8
NA
NA
NA
NA
NA

93.9
NA

NA

84.7

Methotrexate
(%)

72.6
78
0
NA
15
68.5
NA
NA

59
2.7

29

AntiTNF(%)
28.8

Jittawattanarat et al. BMC Pediatrics(2024) 24:555
Page 10 of 12

Jittawattanarat et al. BMC Pediatrics(2024) 24:555

with closer monitoring and more aggressive escalation oftherapy when indicated.
There are some limitations in our study. First, thisstudy was a retrospective review of an electronic medical
record. Although the rheumatology clinic had a routine
record form for every visit, it is inevitable that there may
be missing data at certain follow-up time points. Second,as there was a limited number of cases in our study, thismay have affected subgroup comparisons and may nothave been sufficient to achieve statistical significance.
Third, since this was a single-center study in Thailand, it
may not have represented the entire ERA population. A
larger prospective multicenter study is recommended toaddress these limitations. However, this study was conducted in the largest nationwide referral center that represented real-life practice in a developing country, using
JSpADA scores to assess disease activity and responseto treatment, long-term follow-up to explore the natural course of disease, and application of ASAS criteria toclassify ERA patients during adulthood, which could provide useful information for clinicians providing patientcare in the global community.

Conclusion
This study demonstrates that HLA-B27 positive ERA
patients exhibited higher disease activity and higher
disease activity scores within the first year of treatmentcompared to the HLA-B27 negative group. This led tohigher utilization of bridging systemic corticosteroids,anti-TNF, and longer duration of DMARDs, to effectively
control the disease in HLA-B27 positive ERA patients
until remission. Our findings raise awareness of thehigher disease burden among ERA patients with positive HLA-B27 in real world practice. More multicenterprospective studies should be conducted to explore these
aspects of clinical practice in the global community.
Abbreviations
anti-TNF	antitumor necrosis factor
ASAS	Assessment of SpondyloArthritis international SocietyCBC	complete blood count
CRP	C-reactive protein
DMARDs	disease-modifying antirheumatic drugs
ERA	enthesitis-related arthritis
ESR	erythrocyte sedimentation rate
HLA-B27	human leukocyte antigen B27
ILAR	International League of Associations for Rheumatology
IQR	interquartile range
JIA	juvenile idiopathic arthritis
JSpADA	Juvenile Spondyloarthritis Disease Activity
NSAIDs	non-steroidal anti-inflammatory drugs
SD	standard deviations
VAS	visual analog pain scale
Acknowledgements
We would like to thank Dr. Saowalak Hunnangkul, Ph.D. from the Research
Department of the Faculty of Medicine Siriraj Hospital, Mahidol University,
for the valuable advice and assistance in statistical analysis, and Dr. Mark
Simmerman, Ph.D. from Siriraj Medical Research Center (SiMR) for the
professional English language editing of this manuscript.

Page 11 of 12

Author contributions
BJ conceptualized and designed the study, collected and analysed the data,interpreted the results, drafted the manuscript, reviewed and revised themanuscript. SC and ST contributed in conceptualization and study design,collected and analysed the data, interpreted and summarized the results,
reviewed and critically revised the manuscript with suggestions, and areessentially intellectual contributors. MS conceptualized and designed thestudy, collected and analysed the data, interpreted and summarized theresults, drafted the manuscript, reviewed and critically revised the manuscriptwith suggestions, and is the corresponding author. The authors meet thecriteria for authorship as recommended by the International Committee ofMedical Journal Editors, accept responsibility for the integrity of the work as
a whole, contributed to the writing and reviewing of the manuscript, andhave approved the final version of the manuscript to be submitted for journal
publication.
Funding
Open access funding provided by Mahidol University. This research did notreceive any specific grant from funding agencies in the public commercial or
non-profit sectors.
Open access funding provided by Mahidol University
Data availability
The datasets used and/or analysed during the current study are available
upon reasonable request by contacting the corresponding author.

Declarations
Ethics approval and consent to participate
The study protocol was approved by the Ethics Committee for Research in
Humans of the Siriraj Institutional Review Board of the Faculty of Medicine
Siriraj Hospital, Mahidol University (Certificate of Approval number Si
359/2022). Due to the retrospective study design, the informed consent andassent were waived by the Siriraj Institutional Review Board.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1
Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol
University, Bangkok, Thailand
2
Division of Rheumatology, Department of Pediatrics, Faculty of Medicine
Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi,
Bangkok 10700, Thailand
3
Division of Rheumatology, Department of Pediatrics, Faculty of Medicine
Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand
Received: 17 February 2024 / Accepted: 23 August 2024

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