Abstract
Objective
Referrals to pediatric rheumatology clinics encompass a broad range of clinical scenarios, including cases prompted by abnormal laboratory findings in the absence of clear clinical suspicion for rheumatic disease. This study aimed to evaluate the clinical characteristics and diagnostic outcomes of children referred for abnormal laboratory results.
Methods
This retrospective study included pediatric patients evaluated at the pediatric rheumatology clinic of our institution between April 2025 and February 2026 who were referred for abnormal laboratory results without definite clinical suspicion of rheumatic disease. Demographic features, referral indications, laboratory findings, clinical characteristics, and final diagnoses were recorded. Patients with previously established rheumatic disease were excluded. Statistical comparisons were performed between patients with and without rheumatologic diagnoses.
Results
A total of 123 patients were included. The median age was 7 years (range 1-18), and 52.8% were female. Diagnostic testing had been initiated without symptoms in 26% of patients. Overall, 23.6% received a rheumatologic diagnosis, while 76.4% were classified as having non-rheumatologic conditions. Periodic fever syndromes and juvenile idiopathic arthritis were the most common rheumatologic diagnoses. Healthy children and allergic diseases represented a substantial proportion of the non-rheumatologic outcomes. Male sex, fever, arthritis, elevated acute-phase reactants, and decreased complement levels were significantly associated with a rheumatologic diagnosis, whereas isolated arthralgia and myalgia were more frequent in non-rheumatologic cases.
Conclusion
Most children referred because of abnormal laboratory findings did not receive a rheumatologic diagnosis. Objective inflammatory findings were more predictive of true rheumatic disease than isolated laboratory abnormalities. A symptom-based approach to testing and referral may improve diagnostic accuracy and reduce unnecessary specialist consultations.
Introduction
Pediatric rheumatic diseases (PRDs) are autoinflammatory or autoimmune conditions that can affect multiple organs and systems, primarily the musculoskeletal system, connective tissues, and vascular structures. The true prevalence of PRDs is not precisely known and varies across geographic regions(1). Although an estimated 6-7 million children worldwide are affected, the number of pediatric rheumatologists remains insufficient globally(2). As for Türkiye, pediatric rheumatology is a developing subspecialty, and the country’s genetic and geographic background contributes to a relatively high frequency of autoinflammatory diseases(3).
Children suspected of having rheumatic disease often present with nonspecific complaints, leading to frequent referrals to pediatric rheumatology clinics. However, previous reports indicate that only approximately half of referred patients ultimately receive a rheumatic diagnosis(4, 5). In daily practice, referrals are frequently triggered by isolated laboratory abnormalities that are not supported by compatible clinical findings. Such referrals may cause unnecessary family anxiety, delay the appropriate evaluation of other conditions, and increase the healthcare burden.
Given the limited availability of specialists and the increasing demand for consultations, distinguishing clinically meaningful laboratory findings from incidental test positivity is essential. Better characterization of these referrals may improve referral accuracy and optimize healthcare utilization. Therefore, this study aimed to evaluate the characteristics and clinical outcomes of children referred to pediatric rheumatology clinics for abnormal laboratory findings.
Materials and Methods
This retrospective study included pediatric patients who were evaluated at the pediatric rheumatology clinic of our institution between April 2025 and February 2026 after being referred for abnormal laboratory results in the absence of a definite clinical suspicion of rheumatic disease.
Abnormal laboratory findings were defined as any positive or elevated rheumatologic or inflammatory laboratory parameter detected prior to referral. Because laboratory cut-off values may vary between centers, these findings were interpreted according to the reference ranges and cut-off values of the referring institution. Patients with a previously established diagnosis of rheumatic disease, patients referred primarily due to clinical findings suggestive of rheumatic disease (e.g., persistent arthritis, vasculitic rash, serositis), patients with a follow-up period shorter than six months, and patients with incomplete medical records were excluded from the study.
All patients had undergone a comprehensive evaluation by an experienced pediatric rheumatologist, including a detailed medical history and a complete systemic and musculoskeletal physical examination. All pathological findings were documented in standardized medical records. Data extracted from patient files were recorded in a standardized case report form and included demographic characteristics, clinical features, referral indications, laboratory parameters (including the abnormal test results prompting referral), final diagnoses, and clinical outcomes.
All procedures were performed in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the University of Health Sciences Türkiye, İzmir Tepecik Education and Research Hospital Ethics Committee (approval no: 2025/03-30, date: 10.04.2025). Prior to inclusion in the study, written informed consent was obtained from each participant’s parent or legal guardian.
Statistical Analysis
Data analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 25.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were presented as mean ± standard deviation or median (min-max) for continuous variables, and as number (percentage) for categorical variables. The normality of the distribution was assessed using the Kolmogorov-Smirnov test. Comparisons between groups were performed using the independent samples t-test or Mann-Whitney U test for continuous variables, and the chi-square test or Fisher’s exact test for categorical variables, as appropriate. A p-value of <0.05 was considered statistically significant.
Results
A total of 123 patients were included in the study. The cohort comprised 65 females (52.8%) and 58 males (47.2%), with a median age of 7 years (range: 1-18 years) and a median follow-up duration of 7 months (range: 6-14 months). Most referrals originated from general pediatrics and primary care/family health centers. Baseline demographic characteristics, referral sources, indications, and presenting clinical features are summarized in Table 1.
The most common referral indication was heterozygous Mediterranean Fever (MEFV) gene mutation positivity, followed by antinuclear antibodies (ANA) positivity, elevated antistreptolysin O (ASO) titers, and increased acute-phase reactants (APR), whereas complement abnormalities, urinary findings, and cytopenias were less frequent (Table 1).
Diagnostic testing was initiated in 26% (n=32) of patients without symptoms, whereas 74% (n=91) underwent testing because of at least one clinical complaint. Among symptomatic patients, musculoskeletal manifestations were the most frequent, followed by fever, aphthous stomatitis, rash, and abdominal pain (Table 1).
Final diagnoses during follow-up are summarized in Table 2. Overall, 23.6% (n=29) of patients received a rheumatologic diagnosis, whereas the majority (76.4%, n=94) received a non-rheumatologic diagnosis. Among rheumatologic diseases, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome and juvenile idiopathic arthritis (JIA) were the most common diagnoses. Notably, 13.3% of patients carrying a heterozygous mutation in the MEFV gene exhibited clinical features of Familial Mediterranean fever (FMF) or evidence of subclinical inflammation. Within the non-rheumatologic group, healthy children made up the largest proportion, followed by those with allergic disorders, vitamin D deficiency, hypermobility, and infections; other diagnoses occurred less frequently (Table 2).
Among the 29 patients ultimately diagnosed with a rheumatologic disease, 13.8% (n=4) had been tested while asymptomatic, whereas 86.2% (n=25) had been tested because of at least one clinical symptom (p=0.08). Although the difference did not reach statistical significance, rheumatologic diagnoses were proportionately more frequent among symptomatic patients (Table 3).
When patients with and without a rheumatologic diagnosis were compared with respect to clinical, laboratory, and demographic characteristics, male sex, fever, arthritis, elevated APR, and decreased complement component 3 (C3) levels were significantly more frequent in patients with a rheumatologic diagnosis, whereas arthralgia and myalgia were significantly more common among those without a rheumatologic diagnosis (Table 3). No significant differences were observed between the two groups regarding mucocutaneous symptoms, abdominal pain, or rash. Likewise, consanguinity, family history of rheumatic disease, and laboratory parameters-including cytopenia, hematuria, and proteinuria; elevated ASO and creatine kinase levels; rheumatoid factor (RF) levels; human leukocyte antigen B27 (HLA-B27) positivity; and ANA positivity-did not differ significantly between the groups (data not shown).
Discussion
This study evaluated the diagnostic yield and clinical outcomes of children referred to pediatric rheumatology primarily because of abnormal laboratory findings. Only 23.6% of referred patients ultimately received a rheumatologic diagnosis, a rate substantially lower than previously reported national and international figures. While earlier studies reported diagnostic yields between 40% and 73%(6-8), our findings align more closely with recent data specifically examining laboratory-driven referrals, in which approximately 30% of patients received a rheumatologic diagnosis(9). While early referral remains essential in suspected inflammatory disease, our findings suggest that indiscriminate testing in the absence of clinical suspicion may reduce diagnostic efficiency.
The predominance of non-rheumatologic and even healthy outcomes in our cohort highlights a critical issue in pediatric practice: laboratory abnormalities in children frequently lack specificity when interpreted outside an appropriate clinical context. Incidental positive laboratory findings often coexist with common pediatric conditions, lowering pretest probability and inflating referral rates. Although periodic fever syndromes and inflammatory arthritis accounted for most confirmed rheumatologic diagnoses, these conditions remain fundamentally clinical diagnoses and are best identified through structured history and examination rather than by laboratory screening alone.
Referrals were most frequently triggered by positivity for heterozygous MEFV mutation, ANA, or elevated ASO titers. In regions such as Türkiye, where FMF prevalence and carrier frequency are high(10), widespread genetic testing may increase the risk of overinterpreting heterozygous variants. However, FMF remains primarily a clinical diagnosis, with genetic findings serving a supportive role(11). Although a subset of heterozygous carriers in our cohort met diagnostic criteria based on compatible clinical features and subclinical inflammation, most carriers did not meet these criteria. As emphasized in European Alliance of Associations for Rheumatology/Paediatric Rheumatology European Society recommendations(12), the marked phenotypic heterogeneity of FMF and the complexity of variant interpretation necessitate expert clinical judgment. These findings reinforce that heterozygosity alone should not be considered diagnostic in the absence of clinical correlation.
ANA positivity did not differentiate between patients with and without rheumatologic disease in our cohort. Although ANA is classically associated with connective tissue diseases, particularly systemic lupus erythematosus, its prevalence may reach up to 15% in otherwise healthy children(13, 14). Furthermore, a national cohort study of children referred exclusively for ANA positivity reported that none developed ANA-associated rheumatic disease during more than four years of follow-up(15). Notably, in our cohort, ANA positivity among non-rheumatologic conditions was most frequently observed in children with allergic diseases, a finding consistent with previous reports demonstrating ANA reactivity in atopic populations(16). These observations underscore that ANA testing, when used indiscriminately, has limited specificity and may contribute to over-referral.
A comparable pattern was noted for other commonly requested tests, including ASO, RF, and HLA-B27. ASO levels rise about one week after infection, peak within three to five weeks, and may remain elevated for several months. Interpretation of streptococcal serology can be challenging in regions where group A streptococcal infections are common, as a positive ASO titer often reflects prior exposure rather than active rheumatic pathology(17, 18). Therefore, isolated ASO positivity in the absence of compatible clinical findings should not be considered evidence of rheumatic disease. Likewise, RF and HLA-B27 are primarily used for subclassifying JIA after a clinical diagnosis has been established and have limited value as screening tools(19). Our findings suggest that ordering these tests in the absence of objective inflammatory findings may create diagnostic ambiguity rather than clarity.
In our study, objective inflammatory and immunologic findings-including fever, arthritis, elevated APR, and decreased C3 levels-were significantly associated with confirmed rheumatologic disease, whereas isolated arthralgia and myalgia were more common in non-rheumatologic cases. These findings highlight the critical importance of objective inflammatory markers in distinguishing true immune-mediated disorders from non-specific complaints. Fever, arthritis, and elevated inflammatory markers reflect ongoing systemic inflammation and substantially increase the likelihood of an underlying rheumatologic condition(20). In contrast, isolated arthralgia and myalgia, particularly in the absence of laboratory evidence of inflammation, are common in childhood and are more frequently attributable to benign, mechanical, infectious, or functional etiologies. The differential diagnosis of pediatric musculoskeletal pain is broad and includes orthopedic, infectious, inflammatory, and malignant conditions(21, 22). Therefore, careful assessment of pain characteristics such as morning stiffness, objective joint swelling, limitation of movement, and response to activity is essential to determine whether the pattern is inflammatory(23). Collectively, our findings reinforce that clinical reasoning grounded in inflammatory pattern recognition appears far more predictive than reliance on isolated laboratory abnormalities.
Study Limitations
This study has limitations inherent in its retrospective single-center design. Referral practices may reflect local patterns and disease prevalence; follow-up duration, although sufficient for most diagnoses, may not fully exclude late-onset disease in a minority of patients. Nevertheless, the study provides real-world data from a high-prevalence autoinflammatory setting and specifically addresses laboratory-driven referral patterns, a topic that remains underexplored.
Conclusion
Pediatric rheumatology encompasses a broad range of clinical presentations, including referrals prompted solely by laboratory abnormalities. In our cohort, most children referred for abnormal test results did not receive a rheumatologic diagnosis. Objective inflammatory, findings such as fever, arthritis, and elevated APR, were more predictive of true rheumatic disease than isolated laboratory abnormalities or non-specific pain complaints. In settings where genetic and autoantibody testing is widely available, laboratory-driven referrals may reduce pretest probability and increase healthcare burden. A symptom-based approach to testing and referral is therefore essential to improve diagnostic accuracy and minimize unnecessary specialist consultations. While early referral remains crucial in suspected inflammatory disease, indiscriminate testing without clinical suspicion may compromise diagnostic efficiency.
