Anemia in Juvenile Idiopathic Arthritis (JIA) and Other Pediatric Rheumatologic Diseases: A Retrospective Study

Objectives: The present study estimated the prevalence of anemia among children and adolescents with pediatric rheumatological diseases in a referral center, and analyzed the associated clinical and biological parameters. Methods: A retrospective chart review included 49 children with rheumatological diseases, who were diagnosed by a pediatric rheumatologist and classified according to the International League of Associations for Rheumatology (ILAR) guidelines and criteria endorsed by the American College of Rheumatologists. Anemia was defined as hemoglobin level lower than the 5th centile for the corresponding age and gender. Disease activity was indicated by serum levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), where available. Results: Participants were aged 2 18 years (mean ± SD = 10.41 ± 4.23 years), 38 (77.6%) of them had JIA, and 8 (16.3%) had systemic lupus erythematosus. The most frequent subtype of JIA was the polyarticular (16 out of 38, 42.1%), followed by systemic (14, 36.8%). The prevalence of anemia was 46.9% (95% CI = 32.5% 61.7%), with no significant difference between JIA and other diseases or between the different JIA subtypes. Nevertheless, anemia was more frequently observed in younger patients (age 2 6 years: 69.2% vs <48%) and those with elevated ESR (68.8% vs 33.3%) or CRP (60.0% versus 45.2%), compared with their counterpart respectively; however, only the association with ESR was statistically significant (p = 0.049). No agreement was found between CRP and ESR (Kappa = 0.140). Conclusion: Anemia is frequent in JIA and other rheumatologic diseases in children, concerning approximately 50% of the patients and responding to anemia of inflammation as the major pathophysiological mechanism. Further research is warranted to provide more accurate insight into the pathophysiological mechanisms and clinical characteristics of anemia in pediatric rheuHow to cite this paper: Albokhari, S.M. and Muzaffer, M. (2021) Anemia in Juvenile Idiopathic Arthritis (JIA) and Other Pediatric Rheumatologic Diseases: A Retrospective Study. Open Journal of Rheumatology and Autoimmune Diseases, 11, 188-202. https://doi.org/10.4236/ojra.2021.114019 Received: October 5, 2021 Accepted: November 14, 2021 Published: November 17, 2021 Copyright © 2021 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access S. M. Albokhari, M. Muzaffer DOI: 10.4236/ojra.2021.114019 189 Open Journal of Rheumatology and Autoimmune Diseases matological disease and to measure its morbidity, to provide efficient and evidence-based management strategies.

tinal manifestations [20], in addition to autoimmune hemolytic anemia [21]. Hence, anemia in rheumatological diseases is multifactorial and potentially severe and may be indicative of a malignancy or a premalignancy state [22].
In the present study, we attempted to estimate the prevalence of anemia among pediatric patients with JIA and other rheumatological diseases in a referral center and to analyze its association with the diagnosis, disease severity and activity, as well as the other clinical parameters.

Methods
A retrospective chart review involved all children aged 0 -18 years who were diagnosed and followed up for JIA or other rheumatological diseases at the Pediatric Department of King Abdulaziz University Hospital, between February and October 2020. Children who had no hemoglobin results in their files were excluded. The study was performed in accordance with the ethical standards stated in the 1964 Declaration of Helsinki and its later amendments, and the study protocol was reviewed and approved by the ethical committee of King Abdulaziz University.

Case Definition
The diagnosis of JIA was made by a pediatric rheumatologist on a clinical picture of arthritis in one or more joints occurring for 2 weeks or more in a child aged 16 years or younger, with negative etiological investigation and after ruling out all differential diagnoses. The ILAR criteria were followed for the classification of each case as the appropriate subtype [19]. The diagnosis and classification of the other rheumatological diseases were made based on the criteria endorsed by the American College of Rheumatology (ACR), as available in their official website at: https://www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria.

Laboratory Procedures
Total hemoglobin concentration was measured using the CBC machine (SYSMEX), on blood samples collected in ethylenediaminetetraacetic acid (EDTA) tubes and in compliance with the standard procedures recommended by the manufacturer. Results are given as hemoglobin concentrations in g/dL. CRP was measured using Alinity (ABBOTT) on blood samples collected in (NaHep) tubes and in compliance with the standard procedures recommended by the manufacturer. Results are given in mg/L. ESR was measured using the ESR Analyzer device (BD), on blood samples collected in EDTA tubes and in compliance with the standard procedures recommended by the manufacturer. Results are given in mm per hour (mm/hr).
Abnormal CRP results were defined as values (mg/L) higher than the 97th percentile with respect to the child's age and gender. These percentiles ranged between 3.4 -5.5 mg/L in females and 2.6 -5.3 mg/L for males [24]. Abnormal ESR was defined as level > 20 mm in the first hour.

Statistical Methods
Statistical analysis was performed with the Statistical Package for Social Sciences version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). Categorical variables are presented as frequency and percentage, while continuous variables are presented as mean ± standard deviation (SD). The agreement between CRP and ESR in indicating active inflammatory state was analyzed using Kappa coefficient. Kappa value was interpreted as no agreement (<0), slight (0 -0.20), fair (0.21 -0.40), moderate (0.41 -0.60), substantial (0.61 -0.80) and perfect (0.81 -1.0) agreement [25]. A p-value of <0.05 was considered to reject the null hypothesis.

Participant Characteristics
Forty-nine children were included in the study, 28

Biological Assessments and Screening for Anemia
Inflammatory markers showed elevation in ESR and CRP in 16

Clinical and Biological Factors Associated with Anemia
There was no statistically significant difference (p = 0.425) in the prevalence of anemia between JIA (50.0%) and other rheumatological diseases (36.4%). On the other hand, although not statistically significant, oligoarthritic JIA had a

Summary of Findings
This retrospective study showed that anemia is common among children with rheumatological diseases, accounting for approximately 50% in JIA and 36.4% for other diseases, and its prevalence was likely to be decreasing with age. Anemia of inflammation was likely to be the major mechanism of anemia, and the prevalence of anemia was significantly associated with elevated ESR levels, while it was not associated with CRP level. The combination of the two markers showed even higher frequency of anemia (71.4%) in case of elevation of both markers; however, this was not statistically significant. Further, children with oligoarthritic subtype were likely to have a higher prevalence of anemia. On the other hand, findings from this chart review suggest that approximately 50% of anemia cases did not benefit from the appropriate management. The discussion section will focus on JIA as the most prevalent diagnosis in our study sample.

Anemia in Children with JIA and Other Rheumatological Diseases: Prevalence and Mechanisms
Anemia is a frequent systemic complication in children with JIA or other rheumatological diseases and may respond to different pathological mechanisms. The most common pathophysiologic mechanism is anemia of inflammation. It is more frequently reported in systemic-onset JIA, where it is usually microcytic, due to defect in iron supply for erythropoiesis [25] [26] [27]. However, this defect is usually due to iron accumulation in the reticuloendothelial system and is often S. M. Albokhari, M. Muzaffer  associated with increased serum transferrin receptor (TfR). These abnormalities are believed to be the effect of increased TNF-α, which has an inhibitory action on erythropoiesis and may cause apoptosis of bone marrow erythroid cells in the long term. A study showed that anti-TNF therapy improved iron status of anemic JIA children, as it restored the hemoglobin levels and mean corpuscular volume of red blood cells (MCV) [28].
In JIA, anemia occurs often during disease onset or exacerbation, and sometimes in conjunction with other more severe extra-articular manifestations such as pericarditis and myocarditis [29]. Among the other mechanisms by which JIA is suspected to induce chronic anemia in JIA is the frequent presence of subclinical gastrointestinal lesions, notably due to Helicobacter pylori, which could only be evidenced in endoscopy [30]. Other cases of anemia in JIA may be indicative of malignancy, which suggests that the highest attention should be given to anemic patients in order to address the etiology [22]. Therefore, anemia among JIA patients should be promptly recognized and properly managed.

S. M. Albokhari, M. Muzaffer Open Journal of Rheumatology and Autoimmune Diseases
In the present study, anemia was found in 47% of children with rheumatic diseases, all of them were likely not in exacerbation phase. By focusing on JIA, although not statistically significant, the prevalence of anemia was relatively higher in patients with oligoarthritic subtype compared to those with other subtypes including systemic. This may be due to patients with systemic JIA being more often treated for anemia. In 2015, a previous study conducted in our center, and coauthored by the two authors of the present study, anemia was found in 59.8% among a cohort of 82 JIA children, representing the most frequent biological abnormality. However, the study did not analyze the correlation of anemia with disease subtype or activity [19]. Internationally, a study from Thailand explored the hematological characteristics of 55 newly diagnosed JIA children and reported even higher percentage (83.6%) of anemia cases, 86.9% of which were anemia of inflammation and 8.6% required transfusion. The same study showed that children with systemic JIA were more exposed to anemia and had lower levels of hemoglobin than other subtypes [17]. By comparison, this extremely high prevalence of anemia in newly diagnosed JIA children may support the relatively higher prevalence found in younger children that were found in our study, which may correspond to an early phase of the disease confounded by the patient's age. Altogether, these data are concordant with regards to the high prevalence of anemia of inflammation in JIA and other rheumatological diseases; however, further research is warranted to explore its pathophysiological and clinical characteristics, along with its prognostic value and determine the evidence-based management strategies.

Inflammatory Markers, Disease Activity and Anemia
The evaluation of patients with rheumatological diseases requires differentiating active from inactive state of the disease, as these diseases are characterized by flare-ups and remission phases. Regular assessment of disease activity is a crucial step of the clinical assessment of afflicted children, as it provides key indications on the functional prognosis, efficacy of the antirheumatic drugs and patient's well-being. In case of JIA, several criteria have been proposed to provide an accurate estimate and enable overtime monitoring of the level of disease activity in a given patient. Earlier, in 2009, the Juvenile Arthritis Disease Activity Score (JADAS) used four criteria: 3 clinical and one biological criterion. The clinical criteria included the physician's global assessment and patient/parent's global scoring of well-being, both using a 0 -10 scale, as well as the active joint count. The biological parameter consisted of ESR level, which was normalized to a 0 -10 scale. The JADAS was proposed in three versions, JADAS-71, JADAS-27 and JADAS-10, which differed by the number of joints to be assessed. All of the versions were demonstrated to be valid in discriminating disease activity and adapted for clinical use. However, according to the developing team, the use of ESR instead of CRP was motivated by its availability in the data sets where the score was validated [31] [32]. Subsequently, in 2011, a Nordic team has tested the validity of using CRP as an alternative to ESR in JADAS and found excellent Open Journal of Rheumatology and Autoimmune Diseases correlation of the modified score with the original one (r = 0.99), in addition to comparable validity, discriminative ability and sensitivity to change [33]. However, a study by Mcerlane et al. evaluated the validity of using only the 3 clinical criteria of the JADAS, with exclusion of the ESR. By applying the three modified versions of JADAS on 352 newly diagnosed JIA children with different ILAR subtypes of the disease, authors observed improved construct validity with respect of the three clinical criteria, while ESR did not correlate well with the original or modified score. Authors suggested that the exclusion of the laboratory criterion, ESR, would improve the feasibility and clinical applicability of the scale [34]. On the other hand, the American College of Rheumatology (ACR) recommendations adopted, in 2011, a more simplified algorithm using the same criteria of JADAS, thereby stratifying JIA disease activity into three levels including low, moderate and high disease activity. Thus, the ACR used ESR but not CRP, in addition to the three other clinical criteria [35]. Other studies demonstrated that CRP and ESR levels, as well IgA rheumatoid factor, were significant indicators of JIA disease activity, all being associated with active synovitis, while other biomarkers such as anti-cyclic citrullinated peptide (anti-CCP) antibodies and cartilage oligomeric matrix protein (COMP) were associated with joint damage [36]. These observations support the interchangeable use of CRP and ESR in measuring the disease severity using composite scores.
In the present study, we observed a significant, two-fold increase in the prevalence of anemia in case of elevation of ESR, while elevated CRP was associated with non-significant 25% increase in anemia. However, in absence of the clinical criteria of disease activity, which constitutes a limitation for this study, the elevation of ESR should be interpreted with caution in the context of anemia. Indeed, anemia constitutes a factor that increases ESR owing to the fact that reduced hematocrit alters the upward flow of blood plasma resulting in faster aggregation of erythrocytes [37]. Thus, the reliability of using ESR as the sole indicator of disease activity is highly questionable in case of anemia. This suggests that the significant association of anemia with ESR that was found in the present study is more probably due to ESR being caused by anemia. On the other hand, when combining ESR with CRP, we observed a substantial increase in the prevalence of anemia when both markers were elevated. Nonetheless, the latter finding was not statistically significant, probably due to the small sample size inducing type II error and reducing the power of the subgroup analysis. On the other hand, there was no agreement between ESR and CRP in indicating inflammation in the present cohort, and the agreement coefficient Kappa dropped from 0.140 to 0.024 in anemic patients with reference to the total study population. As a consequence, the validity of using ESR in composite scores measuring JIA disease activity, in case of anemia, should be further analyzed and may be substituted by CRP or other reliable inflammatory biomarkers.

Limitations
This study has some limitations that may impede the interpretation and genera-S. M. Albokhari, M. Muzaffer Open Journal of Rheumatology and Autoimmune Diseases lizability of the results. The analysis of the correlation of anemia with disease activity was made difficult by the absence of clinical criteria enabling the calculation of severity and disease activity, such as the JADAS score. The significantly increased ESR level in anemic patients is probably the effect of anemia rather than being the effect of inflammation. Missing data about serum ferritin in approximately 50% of anemic patients hindered the exploration of the anemia mechanism. As such, the absence of data on hemoglobin electrophoresis in the majority of patients may also constitute a limitation in a population with a relatively high incidence of hemoglobinopathies. Other factors of anemia were not available such as disease duration, which would provide further insight into the issue.

Conclusion
Anemia is frequent among children with JIA and other rheumatological diseases, concerning approximately 50% of the patients and responding to anemia of inflammation as the major pathophysiological mechanism. It is likely to be more frequent at younger age and or in the early phase of the disease, as well as during disease exacerbations. The use of ESR levels in composite scoring methods measuring disease activity should be reviewed in anemic patients, given the independent association of anemia with high ESR levels. A scoring system for JIA activity including CRP or other inflammation biomarkers should be explored. Further research is warranted to provide more accurate insight into the pathophysiological mechanisms and clinical characteristics of anemia in JIA and other rheumatological diseases, measure its morbidity and provide efficient and evidence-based management strategies.