Ethnic heterogeneity of juvenile arthritis in the Republic of Sakha (Yakutia) related to a high human leukocyte antigen B27 frequency

Abstract

BACKGROUND

Prevalence of the main rheumatic diseases in the Republic of Sakha (Yakutia) [RS(Y)], one of the regions of the Russian Federation, differs from the other regions of the Russian Federation due to its ethnic and geographic features. Knowledge regarding the prevalence and structure of juvenile idiopathic arthritis (JIA) allows us to shape the work of the pediatric rheumatology service in the region correctly, and optimize the healthcare system and the need for medications.

AIM

To describe the epidemiological, demographic, clinical, and laboratory characteristics of children with JIA in the RS(Y) and evaluate the main outcomes.

METHODS

This retrospective cohort study assessed all the data from the medical histories of the patients (n = 225) diagnosed with JIA (2016-2023) in the Cardiorheumatology Department of the M.E. Nikolaev National Center of Medicine. Pearson's χ² test, Fisher's exact test, Mann–Whitney and Kruskal-Wallis tests were used for statistical analyses.

RESULTS

The ethnic prevalence of JIA is higher in Sakha than in Russian children at 110.1 per 100000 children and 69.4 per 100000 children, respectively. The prevalence of JIA among boys and girls in Sakha was similar, unlike in Russians, where the number of girls predominated. The JIA categories were as follows: (1) Systemic arthritis: 3.5%; (2) Oligoarthritis (persistent and extended): 33.8%; (3) Rheumatoid factor (RF) (+) polyarthritis: 0.9%; (4) RF (-) polyarthritis: 14.7%; (5) Enthesitis-related arthritis (ERA): 44%; and (6) Psoriatic arthritis: 3.1%. Prevalence of the ERA category was 4.4 times higher in Sakha children, but the prevalence of systemic arthritis was 2.9 times lower compared to Russians (P = 0.0005). The frequency of uveitis was 10.2%, and the frequency of human leukocyte antigen (HLA) B27 was 39.6% in JIA children. Biologic treatment was received by 40.4% of JIA children and 45.3% achieved remission.

CONCLUSION

Higher JIA prevalence, male and ERA predominance, related to a higher frequency of HLA B27 are typical in RS(Y). These data might improve the pediatric rheumatology health service.

Key Words: Juvenile idiopathic arthritis; Human leukocyte antigen B27; Seronegative spondyloarthritis; Enthesitis-related arthritis; Epidemiology; Arthritis; Yakutia; Sakha; Human leukocyte antigen B27-associated arthritis; Ethnic variation

Core Tip: The prevalence of juvenile idiopathic arthritis (JIA) and other rheumatic diseases in Sakha children is higher than in White/Caucasians, living in the Republic of Sakha (Yakutia). JIA in Sakha children has a unique course related to male prevalence, high frequency of human leukocyte antigen B27 in healthy people and in patients with arthritis, and a high frequency of enthesitis-related arthritis.

INTRODUCTION

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood[1]. According to the current International League of Associations for Rheumatology (ILAR) classification, the disease is represented by 7 categories, which differ in pathogenesis, features of articular involvement, and extra-articular manifestations[2]. The incidence and prevalence of JIA are very heterogeneous and depend on the geographic, ethnic, and genetic characteristics of the population[3,4]. Different JIA categories are associated with different human leukocyte antigen (HLA) loci and environmental factors might influence JIA epidemiology[5]. Ten to twenty years ago, epidemiological studies mentioned the lower incidence of JIA in the Asian populations, compared to Europeans[6,7]. The prevalence differed more than 100 times between Japan (0.83 per 100000 children) and Taiwan (3.8 per 100000 children in Taiwan) and one Australian community-based study (400 per 100000)[6,8,9]. Gut microbiome, partially associated with dietary habits, varies in different countries, and is mentioned as one of the possible key factors in the pathogenesis of JIA[10]. The different JIA categories have a different pathogenesis, which requires specific treatment. Systemic JIA requires treatment with interleukin (IL)-1 and IL-6 inhibition, other categories can be treated with TNF-a inhibitors, and IL-17a blockade is relevant for enthesitis-related arthritis and psoriatic arthritis. IL-6 (tocilizumab, olokizumab, and sarilumab) and co-stimulation blockade with abatacept are convenient for rheumatoid factor (RF)-negative and RF-positive polyarthritis[11]. The outcomes of different JIA categories also vary. Historically, the oligoarticular category belongs to a group of JIA classifications with better outcomes, if severe uveitis is absent, and systemic JIA traditionally is in the severe category; however, early biologic treatment may result in a very high-rate of medication-free remission[12]. Knowledge on the prevalence and structure of JIA allows us to shape the work of the regional pediatric rheumatology service correctly, and optimize the healthcare system and the need for medications. The Republic of Sakha (Yakutia) [RS(Y)] is the largest Asian region in Russia in terms of population, with special geographical conditions (arctic area). Asian populations are characterized by a higher prevalence of several rheumatic diseases, such as spondyloarthritis, Takayasu's arteritis, Behcet's disease, systemic lupus erythematosus, and Kawasaki disease[13].

The present study aims to describe the epidemiological, demographic, clinical, and laboratory characteristics of children with JIA in the RS(Y), characterizing therapy and evaluating the main outcomes.

MATERIALS AND METHODS

Study design and patient selection

In this retrospective cohort study, data from the medical histories of all patients diagnosed with JIA who underwent examination and treatment in the Cardiorheumatology Department of the Pediatric Center of the Republican Hospital No. 1–National Center of Medicine named after M.E. Nikolaev in 2016-2023 were included.

Inclusion criteria: (1) The diagnosis of JIA was established using the criteria of the ILAR[2]; and (2) Age from 0 year to 18 years

Criteria for non-inclusion in the study: (1) Rheumatic diseases other than JIA; (2) Not limited to systemic lupus erythematosus; (3) Systemic vasculitis; (4) Systemic connective tissue diseases; and (5) Auto-inflammatory diseases.

Data collection

The following data were obtained from the medical histories.

Demographic characteristics: (1) Sex; (2) Date of birth; (3) Year of illness; (4) Region of residence; (5) Ethnicity of patients (self-reported); (6) Family history of rheumatic and immune-mediated diseases; and (7) Provoking factors.

Clinical characteristics: (1) JIA category; (2) Age at JIA onset; (3) Active joints at onset; and (4) Presence of uveitis.

Laboratory characteristics: (1) Complete blood cell count; (2) Erythrocyte sedimentation rate; (3) C-reactive protein at the onset of JIA; (4) Presence of HLA B27; and (5) Presence of antinuclear antibodies (ANA) and RF.

Therapy: (1) All anti-rheumatic therapy was evaluated: Nonsteroidal antirheumatic drugs (NSAIDs); (2) Glucocorticosteroid therapy: Systemic (oral and intravenous) and local (intra-articular injections); and (3) The use of disease-modifying antirheumatic drugs (DMARDs) such as non-biologic (nbDMARDS) and biologic (bDMARDS).

Outcomes: (1) Achievement of arthritis remission according to the criteria of Wallace et al[14]; (2) The date of remission; (3) The presence of a JIA flare; and (4) The date of the flare, and requirement to change the medication (new administration of nbDMARDs or bDMARDS).

Statistical analysis

The sample size was not initially calculated and the missing data were not included in the analysis. Statistical analysis was performed by means of the Statistica 10 software (StatSoft Corporation, Tulsa, OK, United States). All continuous variables were checked for normality using the Kolmogorov–Smirnov test. Quantitative variables were reported as medians and percentiles (25%, 75%) for continuous variables, and as absolute frequencies and percentages for categorical variables. Pearson's χ² test or Fisher's exact test in the expected frequencies < 5 was used to compare categorical variables. Two quantitative variables were compared using the Mann–Whitney test and more than two variables with the Kruskal-Wallis test due to the absence of the normal distribution of quantitative variables. A P value < 0.05 was considered statistically significant.

RESULTS

The epidemiology of JIA in the RS(Y)

The study included 225 patients diagnosed with JIA. The incidence of JIA in children aged from 0 to 17 years significantly increased during the follow-up period from 2016 (5.3 per 100000 children) to 2023 (11.7 per 100000 children). The highest number of new cases was registered in 2021 (15.5 per 100000 children). The maximum incidence of JIA in the RS(Y) increased by 65.8%, 2.9 times over the period 2016-2021. These data are shown in Table 1.

Table 1 The incidence of juvenile idiopathic arthritis in the Republic of Sakha (Yakutia).

Year	Number of JIA cases	Incidence of JIA per 100000 children
2016	14	5.3
2017	26	9.8
2018	24	9.1
2019	22	8.3
2020	18	6.8
2021	31	11.7
2022	26	9.8
2023	41	15.5

JIA: Juvenile idiopathic arthritis.

The prevalence of JIA in the RS(Y) at the end of 2023 was 84.5 per 100000 children: Higher in Sakha than in Russian children at 110.1 per 100000 children and 69.4 per 100000 children and higher in children living in rural areas than in cities (Yakutsk, Neryungri, Mirny) at 102.8 per 100000 children and 73.8 per 100000 children, respectively. The largest number of children with JIA was observed in Yakutsk at 123 (54.7%), followed by the mixed geographical zone at 64 (28.4%), industrial zone at 20 (8.9%), and the Arctic zone at 18 (8%). The Sakha JIA patients had a 4.4 times higher prevalence of enthesitis-related arthritis (ERA) than the Russians (P = 0.00005), with a comparable prevalence of the other categories of arthritis, except the systemic category, the prevalence of which was 2.9 times more common in the Russians (P = 0.00005) (Table 2).

Table 2 Prevalence of juvenile idiopathic arthritis in the Republic of Sakha (Yakutia) in 2023, n (%).

The prevalence of JIA1	Total patients [n (%)/n]1	Sakha (n = 168) [n (%)/n]1	Russians (n = 49) [n (%)/n]1	P value
Population	266/293	596 (57.0)/152	622 (43.0)/70
Living area
Urban	123 (54.7)/73.6	87 (51.8)/139.3	30 (61.2)/45.4	0.258
Rural	102 (45.3)/102.8	81 (48.2)/89.8	19 (38.8)/406.2
Gender
Boys	118 (52.4)/86.8	83 (49.4)/106.6	19 (38.8)/52.7	0.198
Girls	107 (47.6)/81.9	85 (50.6)/113.6	30 (61.2)/86.6
JIA categories2
Systemic arthritis	8 (3.5)/3.0	3 (1.8)/2.0	4 (8.1)/5.7	0.00005
Oligoarthritis	76 (33.8)/28.5	47 (28.0)/30.8	26 (53.0)/36.8
Polyarthritis, RF (-)	33 (14.7)/12.4	25 (14.9)/16.4	8 (16.3)/11.3
Polyarthritis, RF (+)	2 (0.9)/0.8	2 (1.2)/1.3	0 (0.0)/0
Enthesitis-related arthritis	99 (44.0)/37.2	86 (51.1)/56.4	9 (18.4)/12.7
Psoriatic arthritis	7 (3.1)/2.6	5 (3.0)/3.3	2 (4.1)/2.8

¹Per 100000 children.

²According to the International League of Associations for Rheumatology classification[2].

JIA: Juvenile idiopathic arthritis; RF: Rheumatoid factor.

Clinical and demographic characteristics of children with JIA in the RS(Y)

In the RS(Y), the number of males with JIA (n = 118, 52.4%) was slightly more than that in girls (n = 107, 47.6%) with the median age of disease onset at 9 (5, 12) years. A positive family history of immune-inflammatory diseases was observed in 60 (26.7%) children, and in 46 (20.4%) children arthritis was present in their next of kin.

The distribution of patients by JIA categories according to the ILAR categories was as follows: (1) Systemic arthritis: 8 (3.5%); (2) Oligoarthritis: 76 (33.8%); (3) Polyarthritis, RF (negative): 33 (14.7%); (4) Polyarthritis, RF (+): 2 (0,9%); (5) Enthesitis-associated arthritis: 99 (44.0%); and (6) Psoriatic arthritis: 7 (3.1%). The median number of active joints was 4 (2, 24). Large joints of the lower extremities knee, and ankle were most often affected. Sacroiliitis was detected in 43 (19.1%) patients, enthesitis in 34 (15.1%) and cervical spine involvement occurred in 11 (4.9%) children. Psoriasis was detected in 7 (3.5%) children. HLA B27 was detected in 87 (39.6%) children with JIA and ANA in 30/45 (66.7%) children.

Uveitis was diagnosed in 23 (10.2%) patients, 11 (47.8%) girls, and 12 (52.17%) boys with a median onset age of 10 years (4, 17 years). Three patients (13%) had uveitis which preceded joint involvement, three patients (13%) developed uveitis simultaneously with arthritis, and 17 (74%) patients developed uveitis after the onset of arthritis. Thirteen (56.5%) patients had bilateral uveitis. Nine patients (39.1%) with uveitis also carried HLA B27. Detailed data are presented in Table 3.

Table 3 Clinical, demographic, and laboratory characteristics of children with juvenile idiopathic arthritis in the Republic of Sakha (Yakutia), n (%).

Parameters	n = 225
Gender: Boys [n (%)]/girls [n (%)]	107 (47.6%, 95%CI: 41.1-54.1)/118 (52.4%, 95%CI: 45.9-58.9])
Age at JIA onset, medians (25%, 75%)	9 (5, 12)
Family history of immune-inflammatory diseases	60 (26.7%, 95%CI: 21.3-32.8)
Arthritis in the close relatives	46 (20.4%, 95%CI: 15.7-26.2)
JIA categories, International League of Antirheumatic Associations
Systemic arthritis	8 (3.5%, 95%CI: 1.8-6.9)
Oligoarthritis	76 (33.8%, 95%CI: 27.9-40.2)
Polyarthritis, RF (-)	33 (14.7%, 95%CI: 10.6-19.9)
Polyarthritis, RF (+)	2 (0.9%, 95%CI: 0.2-3.2)
Enthesitis-associated arthritis	99 (44.0%, 95%CI: 37.7-50.5)
Psoriatic arthritis	7 (3.1%, 95%CI: 1.5-6.3)
Active joints, medians (25%, 75%)	4 (2, 10)
Sacroiliitis	43 (19.1%, 95%CI: 14.5-24.8)
Enthesites	34 (15.1%, 95%CI: 11.0-20.4)
Uveitis	23 (10.2%, 95%CI: 6.9-14.9)
Psoriasis	7 (3.1%, 95%CI: 1.5-6.3)
Antinuclear antibodies-positivity	30/45 (66.7%, 95%CI: 52.1-78.6)
Human leukocyte antigen-B27 positivity	87/220 (39.6%, 95%CI: 33.3-46.1)
RF-positivity	1 (0.4%, 95%CI: 0.1-2.5)

JIA: Juvenile idiopathic arthritis; RF: Rheumatoid factor.

Information regarding possible JIA triggers was available for 62 (27.6%) of patients: (1) Traumatic injury: 25/62 (40.3%); (2) Acute gastrointestinal infections: 22/62 (35.5%); (3) Acute respiratory infections: 11 (17.7%); and (4) Vaccination: 4 (6.5%). Two main identified triggers, traumatic injury and acute gastrointestinal infections, occurred most commonly in boys (59.1% and 56.0%), in children of Sakha nationality (86.4% and 76.0%), urban residents (63.6% and 56.0%), carriers of the HLA B27 (81.0% and 62.5%, P < 0.001) and patients with ERA (77.3% and 64.0%, P = 0.161), respectively.

Treatment of JIA

At disease onset, all 225 (100%) children with JIA received NSAID therapy, 205 (91.5%) received methotrexate, and 29 (14.1%) of them withdrew the drug due to early intolerance (nausea, vomiting, increased liver enzymes), and 91 (40.4%) children received biological medications.

The first-line biological therapy was Etanercept: 60 (65.9%), followed by (1) Adalimumab: 21 (23.1%); (2) Tocilizumab: 7 (7.7%); (3) Secukinumab: 2 (2.2%); and Abatacept: 1 (1.1%). The time before the first biologic administration was 6 (3, 18) months with remission in 34/86 (39.5%) patients after 8.5 (6, 24) months. Minimal disease activity did not require a switch to another class of biologic in 40/86 (46.5%) patients. Second-line biologic therapy was required in 12 patients (14%): (1) Etanercept: 1 (8.3%); (2) Adalimumab: 5 (41.7%); (3) Tocilizumab: 1 (8.3%); (4) Secukinumab: 2 (16.7%); (5) Abatacept: 1 (8.3%); and (6) Upadacitinib: 2 (16.7%). The time before the second biologic from disease onset was 24 (2, 38) months. Remission following the second biologic was documented in 5/11 (45.5%) patients, with a median time before remission of 6 months, and the remaining six patients (54.5%) achieved minimal disease activity. In total, 39/86 patients (45.3%) achieved complete remission, and minimal disease activity was recorded in 47/86 (54.7%) of the patients. Over the past five years (2019-2023), the maximum number of administrations of biologics occurred in 2022-2023 with a gradually reduced gap from onset to biologics since 2019. Biological treatment for uveitis, associated with JIA was received by 14/23 (60.9%) children. De-novo uveitis was diagnosed in 4/60 (6.7%) children treated with etanercept. Detailed data are presented in Table 4.

Table 4 Therapy of juvenile idiopathic arthritis in children of the Republic of Sakha (Yakutia), n (%).

Therapy	Results (n = 225)
Nonsteroidal antirheumatic drugs	225 (100)
Glucocorticosteroids
Not received	180 (80.0)
Intravenous	11 (4.8)
Oral	5 (2.2)
Intra-articular	22 (9.7)
Sulfasalazine	8 (3.6)
Methotrexate	205 (91.5)
Early methotrexate withdrawal	29/205 (14.1)
Leflunomide	1 (0.4)
Cyclosporine A	5 (2.2)
Patients, treated with biologics	91 (40.4)
The first-line biological drugs
Etanercept	60/91 (65.9)
Adalimumab	21/91 (23.1)
Tocilizumab	7/91 (7.7)
Secukinumab	2/91 (2.2)
Abatacept	1/91 (1.1)
Time to the first biologic, medians (25%, 75%) (months)	6 (3, 18)
Remission on the first biologic	34/86 (39.5)
Time to remission on the first biologic, medians (25%, 75%) (months)	8.5 (6, 24)
De-novo uveitis on etanercept	4/60 (6.7)
Patients, treated with second-line biologic	12/91 (13.8)
The second-line biological drugs
Etanercept	1 (8.3)
Adalimumab	5 (41.7)
Tocilizumab	1 (8.3)
Secukinumab	2 (16.7)
Abatacept	1 (8.3)
Upadacitinib	2 (16.7)
Time to the second biologic, medians (25%, 75%) (months)	24 (2, 38)
Patients with remission on the second biologic	5/11 (45.5)
Time to remission on the second biologic, medians (25%, 75%) (months)	6 (6, 6)

DISCUSSION

This study is the first to report the incidence, prevalence, main demographic, clinical and laboratory characteristics, and treatment outcomes in children with JIA in the RS(Y).

A significant increase in the number of new patients diagnosed with JIA has been noted annually in the RS(Y) compared with other regions in the Russian Federation and other countries such as Germany and Sweden[15,16]. Some authors believe that the increase in the number of patients with immune-inflammatory diseases is a consequence of the coronavirus disease 2019 (COVID-19) pandemic[17]. The decrease in the number of new patients in 2020 was most likely explained by the prolonged isolation and a decreased infectious burden in the population, and the subsequent surge may be explained by repeated cases of COVID-19, which is usually accompanied by immune dysregulation, leading to outbreaks of immune-inflammatory diseases, not only rheumatic diseases; however, these data are contradictory[18,19]

The incidence of JIA in the RS(Y) in the rural population was higher than that in the urban population. Similar data were presented by colleagues from the Republic of Bashkortostan[20]; however, an inverse relationship was noted in Sakha children living in the city who were more likely to develop arthritis. Given the established relationship with infectious agents of arthritis, the high frequency of HLA B27 in the population of Sakha children, a higher population density in the city may explain the higher prevalence of arthritis among city residents. In general, Sakha children had a 1.5 times higher risk of developing arthritis, compared to Russians[21,22]. Thus, arthritis development among Sakha children was 1.5 times higher than in the Russian children. This might be explained by ethnic characteristics as the Sakha ethnic group belongs to Asian populations, in whom the incidence of rheumatic diseases is generally higher than that in European populations[13,21,22]. It was found that the prevalence of systemic lupus erythematosus in Sakha children in the RS(Y) exceeds that in neighboring regions of Russia, where the White/Caucasian population prevails. The prevalence of systemic lupus erythematosus in the RS(Y) in children is 20.2 times higher than that in the Khabarovsk Region and 6.4 times higher than that in the Primorsky Region of Russia[23]. The most interesting feature of JIA distribution in the RS(Y) is the predominance of affected males, with a relatively older age at disease onset, and the peculiarities of the distribution of JIA subtypes. In the RS(Y), due to the predominance of Sakha children among all the patients with JIA, as well as the high prevalence of HLA B27 among the patients with JIA, the leading phenotype in JIA is ERA, which accounts for 44.0% of all cases of arthritis[21,22]. This pattern may be due to the high incidence of HLA B27 among the healthy population of the RS(Y) of 25%, which is typical for Asian populations, where arthritis associated with HLA B27 is the most common, both in adults and children[24-26]. Oligoarthritis, polyarthritis, systemic arthritis, and psoriatic arthritis are relatively rare variants. In the White/Caucasian population, oligoarthritis accounts for up to 50% of all JIA cases, polyarthritis up to 20%-30%, systemic arthritis 10%-15%, psoriatic and enthesitis-associated arthritis 5%-10% of the total number of children with JIA[15]. Similar cases are described in African and Middle Eastern countries[27]. The highest frequency of ERA among countries of the Middle East was described in Turkey and amounts to 32.8%-32.9% in the Western Anatolia region and Istanbul[28,29], while in other Turkish studies, the frequency of ERA ranges from 10% to 21%[30-32]. Turkey also has the highest prevalence of JIA at 64 per 100000 children among countries in the Middle East and Africa[27,33]. ERA is described as the most common variant in several Asian countries, such as India, Pakistan, and Singapore[34-36], whereas in Japan systemic arthritis is the predominant variant[37].

Researchers from Singapore found that ERA is the most common (32.8%) variant of JIA, and is predominant in males (60.6%). A high frequency of HLA B27 was detected among the ERA patients (79.8%) with a low frequency of uveitis (2.8%). These data are similar, except for the frequency of uveitis, to those in European countries[15,36]. In a study in India, the highest frequency of HLA B27 was detected in the ERA JIA category (87%) and was associated with sacroiliitis[38]. HLA B27 was also found among Indian children with oligoarthritis (10.3%), (RF)-positive polyarthritis (16%), RF-negative polyarthritis (26%), psoriatic arthritis (66%), undifferentiated arthritis (40%) and was not found in patients with the systemic variant of JIA. The authors drew attention to the relatively low correlation between the presence of HLA B27 and symptoms typical of ERA, such as lower back pain, enthesitis, and sacroiliitis[29]. HLA B27 was also frequent in Polish JIA children (27.2%), and more frequent in boys (31.6%) than in girls (23.3%). The presence of HLA B27 was associated with slightly older/late JIA onset age, non-biological DMARDs corticosteroid inefficacy, and higher prescribing of biological DMARDs[39]. Similar data were obtained in Bosnia and Herzegovina where HLA B27 patients (60%) had ERA and this antigen was a marker of a more severe/resistant disease course[40]. In a Thai study, 64.4% of ERA patients were HLA B27 positive and had a more active disease course[41]. A quarter of Finish JIA patients were HLA B27 positive with a similar disease profile and poorer outcomes[42]. The data on HLA B27 in Africa are different compared to European and Asian populations. The presence of HLA was highly associated with only the Fula ethnic group in Senegal (87%), although this group encompasses 24% of the population[43]. The prevalence of HLA B27 in this ethnic group is 6%-7.8% compared with the rest of the sub-Saharan African population, which is generally less than 1%[44].

In the United Kingdom, the prevalence of JIA among Asian and Black populations was approximately comparable at 42.1 per 100000 children and 46.3 per 100000 children, respectively, and was significantly lower than that in Whites/Caucasians at 71.1 per 100000 children. The lowest prevalence was recorded in children with mixed origin at 29.4 per 100000 children[45]. It is worth noting that the prevalence of JIA among Sakha children was comparable to data from the Republic of Bashkortostan, but higher than Alaska Indians (79 per 100000 children) and many Asian countries, but lower than that in Germany (133-168 per 100000 children)[15,20,46]. Our study found the same prevalence of JIA among Sakha boys and girls, similar to the indigenous inhabitants of Alaska, and the prevalence of ERA was 4.4 times higher in Sakha children than in Russians[46].

Although psoriasis belongs to the group of diseases associated with spondyloarthritis, its frequency remains low (3.5%), similar to other Asian populations, compared with Whites/Caucasians (6%-8%)[47]. A relatively low incidence of uveitis (10%), especially symptomatic, which was expected to be higher in patients with a high prevalence of HLA B27 was revealed. In general, the frequency of uveitis reflects the worldwide epidemiology, ranging from 19.1% in Northern and 18.8% in Southern Europe, 11.3% in Western Europe and North America, 9.0% in Eastern Europe, 6.4% in Latin America, 5.9% in Africa and the Middle East, and 5% in Southeast Asia[47].

The disease course in Sakha children was more aggressive, and difficult to treat with conventional DMARDs. The majority of JIA patients received methotrexate therapy, with a high level of early intolerance (14.1%) which developed soon after the first weeks of therapy. This may be related to the ethnic peculiarities of xenobiotic detoxification typical in the Sakha population. Insufficient response to non-biological DMARDs, accompanied by poor tolerance, leads to a relatively high frequency (40.4%) and early administration of biological drugs. The predominance of ERA, characterized by the lower efficacy of methotrexate, leads to a faster switch to biologics, which significantly differs from White/Caucasian/European populations, where the time before biologic administration is longer. The highest frequency of biologics is in Northern Europe at 46.0%, followed by North America 38.6%, Southern Europe 34%, Latin America 32.4% and Western Europe 30.5%, and the lowest is in Eastern Europe 25.1%, Africa and the Middle East 24.4% and Southeast Asia 21.1%[47].

The frequency of biologic administration depends on the JIA category and is up to 100% for systemic arthritis, 57.1% for psoriatic arthritis, 49.5% for ERA, 39.4% for polyarthritis, and 22.4% for oligoarthritis (P = 0.0001). The remission rate on biologics is relatively low; however, most of the patients corresponded to the status of minimal disease activity, and did not require changes in current treatment. The rate of remission depended on the JIA category. The highest remission rate (85.7%) was recorded in patients with systemic arthritis, 50% in polyarthritis, and only a third of patients with ERA, oligoarthritis and psoriatic arthritis achieved remission (P = 0.097). The time before biologics administration was the shortest for systemic arthritis at 2.5 (2.0, 6.0) months, followed by ERA at 5.0 (2.0, 12.0) months, polyarthritis at 10.0 (4.5, 24.0) months, oligoarthritis at 12.0 (5.0, 24.0) months and psoriatic arthritis at 15.0 (7.0, 21.0) months (P = 0.047). The peculiarities of JIA epidemiology with predominance of ERA refractory to methotrexate led to the fairly early administration of biologics, which enabled faster control of inflammation. The clinical picture of juvenile arthritis in children of the RS(Y) shows a large number of patients with idiopathic arthritis associated with HLA B27. The frequency of de novo uveitis in patients receiving etanercept corresponds to literature data.

Limitations

Our study has several limitations, which include a retrospective and monocentral study design, loss of some data, ethnic self-distribution, and different times before hospital admission, which may have been dependent on several external factors, and could affect the results of the study. A small sample size increases the risk of Type II errors, where true effects may not be detected. The lack of clear definitions or standardization of ethnicity identification could lead to inconsistencies in data collection and analysis, ultimately impacting the study's conclusions. The remote distances of qualified medical services, as well as rigorous climate and logistic issues may impact early initiation of specialized treatment and outcome results. In our study, we did not evaluate the confounding variables that could influence outcomes, such as the presence of comorbidities, variations in treatment protocols over time, or differences in healthcare access. These factors could skew the results and interpretations. A more comprehensive analysis that accounts for these confounders would provide more robust and reliable findings.

CONCLUSION

JIA in the RS(Y) has its own epidemiological, clinical, and laboratory features associated with the predominance of HLA B27 in the population of Sakha children. Sakha children had a higher JIA prevalence with male predominance, and ERA. Psoriasis is a relatively rare extra-articular manifestation of JIA and the frequency of uveitis was higher than in Asian populations. A more severe disease course, a higher rate of methotrexate inefficacy and intolerance, and higher frequency of biological DMARD administration necessitate changes in the local rheumatology health service for a better understanding of the requirement of specialists and specific treatment.