Comparative analysis of pediatric rheumatic patient growth patterns against norms: A cross-sectional study conducted in an Eastern Indian hospital

Background . Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease. Rheumatic diseases are a major cause of chronic illness in children around the world. SLE is a further prevalent inflammatory illness. Aims and objectives. To study different growth parameters of pediatric patients attending pediatric rheumatology clinic, to compare the growth parameters with age and sex matched controls and to compare growth among different types of pediatric rheumatic patients. Method. Different growth parameters and SMI (for children above 9 years) were recorded for patients attending pediatric rheumatology OPD having disease duration more than one year. Results. Among 121 patients, JIA was most common followed by SLE. Among JIA subtypes, SOJIA is most common. Mean age of presentation was earlier in SOJIA, late in JoAS. SLE patients had larger duration of illness prior to diagnosis than JIA patients. In JIA patients, mean height was significantly less than controls. SOJIA and polyarticular variety had significantly less weight and height compared to controls. SLE patients had significantly less weight and height compared to control. Anthropometric parameters were significantly more in SLE patients compared to JIA cohort. There was significantly more delayed puberty both in JIA and SLE patients compared to controls. Conclusion . JIA was most common, followed by SLE. Among JIA patients SOJIA variety was most common, JIA patients had significantly lower height than controls. SLE patients had significantly lower weight and height than controls. Delayed puberty was significantly more in both JIA and SLE patients compared to controls


INTRODUCTION
A large number of children around the world suffer from rheumatic diseases, the most prevalent of which is juvenile idiopathic arthritis (JIA), which are autoimmune disorders that impact the musculoskeletal system [1].In some children, symptoms start early and last until they reach their full developmental potential [1].Increased disease burden, joint injury, deformity, and delayed growth and development are some of the long-term effects that might result from a delayed diagnosis.
There is a great deal of clinical variability in the course of systemic lupus erythematosus (SLE), a chronic autoimmune illness affecting multiple systems.Despite the prevalence of SLE in adults, around 10% to 20% of cases occur in youngsters.There are some shared characteristics of SLE across age groups, but there have also been some notable distinctions.Compared to SLE that begins in adults, cSLE manifests more severely, progresses more aggressively clinically, and causes damage more quickly [2].
Chronic disease, pharmaceutical side effects, and other comorbidities cause SLE in children and adolescents to progress to adulthood with significant morbidity [2].Out of all the known morbidities, growth failure is specific to cSLE.It can impact people's quality of life and make it hard for them to adapt physically and mentally to living with a chronic illness.A number of issues can arise from juvenile idiopathic arthritis, including growth and pubertal disorders, which can lead to handicap both in the short and long term, as well as a decrease in quality of life.Symptoms of growth failure, which can range from a slowing of the rate of height gain to a complete absence of height altogether, are common in patients with chronic inflammatory diseases.In juvenile inflammatory arthritis (JIA), the frequency of low height ranges from 10.4% in children with polyarticular disease to 41% in patients with the systemic type.In contrast, oligoarthritis is most commonly linked to asymmetrical limb growth in affected areas.Chronic inflammation, long-term corticosteroid usage, malnutrition, changed body composition, delayed pubertal onset, or sluggish pubertal advancement are all factors in the pathophysiology of growth disorders.These factors can have an impact on the growth plate homeostasis and function on a local level, or they can have an effect on the GH/ IGF-1 and GnRH/gonadotropin-gonadic axes systemically.Even though there are novel ways to manage inflammation, 10-20% of those with severe types of the condition still experience stunted growth that ultimately leads to a low stature [4].Delays in puberty are linked to a lower peak bone mass and an increased risk of bone fragility both now and in the future.For a comprehensive evaluation of adolescents with JIA4, it is crucial to track their bone health and puberty progress.Starting at age 9, it is advised that these patients undergo a pubertal stage assessment every six months.It is essential to always take the patient's bone age into account while evaluating linear growth.While the exact effects of rhGH (recombinant human Growth Hormone) treatment on JIA children are yet unknown, research has demonstrated that, when administered at high doses in an anti-inflammatory environment, following steroids and biologic therapy, it can promote a rapid acceleration of growth in the prepubescent years, similar to the catch-up growth response seen in patients lacking GH.This article aims to assist pediatricians in making accurate and early diagnoses of growth and pubertal problems in children with JIA by providing a thorough overview of the mechanisms that contribute to these conditions.

Study design and population
This study was conducted at the pediatric rheumatology OPD (Out Patient Department) of a tertiary hospital in the Eastern Indian metro city of Kolkata with an indoor bed strength of 680.
Pediatric patients with inflammatory arthritis attending the once weekly clinic from 1 st January 2023 to 31 st December 2023 were selected for the study.
The approval of the Institutional Ethics Committee was sought and granted.Parents or legal guardians of children under the age of thirteen were asked to provide written consent.For patients aged 13 years to 16 years, consent was taken with help of an assent form.
For children with symptoms of JIA, diagnosis was done by ILAR (International League of Associations for Rheumatology) classification criteria.For SLE, diagnosis was done by SLICC (Systemic Lupus International Collaborating Clinics) classification criteria.
Inclusion criteria -Consecutive patients with inflammatory arthritis attending pediatric rheumatology OPD with upper age limit of 16 completed years (no lower age limit) having a disease duration of more than one year and willing to be a part of the study.
Exclusion criteria -other causes of joint pain like those with growth pain, hypermobility, pain amplification syndrome, blood dyscrasias, chronic kidney, endocrine or metabolic diseases.

Procedure
This was a cross sectional study of children diagnosed with pediatric rheumatic diseases.
The following growth parameters were recorded: 1. Height 2. Weight 3. Body Mass Index 4. Sexual maturity ratings of children above 9 years of age.Disease activity was assessed using SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) and JADAS 10 (Juvenile Arthritis Disease Activity Score) for SLE and JIA respectively.
The weight was recorded to the closest 0.1 kg using an electronic weighing scale.A wall-mounted stanometer was used to measure height to the closest 0.1 cm.Weight in kilograms divided by height in meters (Kg/m 2 ) is the method used to determine body mass index (BMI).For puberty assessment, staging was carried out according to Tanner criteria.
Then, these parameters were compared with controls.Controls were selected from age and sex matched healthy children without any chronic disease attending general pediatric OPD.
Lastly, the parameters of different rheumatic diseases like JRA, SLE, Scleroderma was compared with controls.

Statistical analysis
For most variables, descriptive analysis was done.Mean with standard deviation (SD) or median with range (where outliers were present) were used to summarize continuous variables.We used Stu-dent's t-test to examine the quantitative variables.For this, the Android app "Statistics Calculator" was used.Numerical variables were related between: 1. Controls and JIA patients 2. SLE patients and controls 3. Different types of JIA patients with controls 4. SLE and JIA patients by Student unpaired t test.It was regarded as statistically important if the p-value was less than 0.05.
J1A and SLE were found to be predominant in number in our cohort, other rheumatic diseases were minimal.So, for ease of statistical analysis, they were not taken into consideration.For this reason, we considered only JIA and SLE to compare with controls and among themselves.4 showing SLE patients had significantly less weight and height compared to controls.BMI value was not significantly different.
In our cohort of SLE patients, short stature (height less 2 SD) was found in 7 patients (38.8%).Among them, 1 patient was male rest females.So, the percentage among males are 100% and females 35.2%.Tables 7 showing though mean weight, height and BMI were significantly higher in SLE patients than in JIA patients.
Among JIA patients, 30 were active on presentation with much higher JADAS 10 score than 57 non active JIA present in the study.
Among SLE patients, 10 were active on presentation with much higher SLEDAI score than 8 non active SLE present in the study.
Another Indian study from same city (Kolkata) [5] didn't find any significant difference of weight, height and BMI among JIA patients and controls.
Growth retardation is a common symptom of juvenile inflammatory arthritis (JIA), a chronic inflammatory illness.Study population, research methodology, etiologic factors, and illness subtypes all play a role in determining the overall severity of such retardation [5].
However, similar to our study, another study from the same city (Kolkata) revealed 66% of patients with JIA were below 3 rd percentile of height for age (CDC 2000 standard).The p value was found to be <0.0001.So, delayed puberty was significantly higher in the JIA cohort than controls.
Among JIA patients, delayed puberty was common among polyarticular and SOJIA varieties.p value was found to be 0.7, so incidence of delayed puberty was not significantly different between the JIA and SLE cohort.

DISCUSSION
In our cross-sectional study, the mean age (Table 3) and duration of illness prior to diagnosis of JIA (71.9% of total cohort) patients (Table 5) were 9 years 1 month and 3.43 ±2.21 years respectively.There was mild male (52.8%) predominance (Table 3).
Our study revealed mean height of JIA patients were less than age and sex matched controls (Table 6A).The difference was not significant for weight and BMI (Table 6A).We compared p value of difference between cohort of JIA patients and controls among three studies (Table 12).Other than our study, one was from same city (Kolkata) and another one from UK.We found p value was not significant in all 3 growth parameters from the Kolkata study and 2 growth parameters from UK study (didn't compare BMI).
In our cross-sectional study, the mean age (Table 3) was 13 years 10 months, and the time period of illness prior to diagnosis of SLE (14.8% of total cohort) patients (Table 5) was 4.39 ±2.25 years.There was a high female (88.8%) predominance.
But the results of another Indian study from Bangalore [12] revealed the mean age to be 13.2 years and duration of illness prior to diagnosis 1 year.
Among international studies, the mean age at diagnosis from a Thailand study [13] (11.3±2.4 years) was nearer to ours.Whereas, the results from Oman [2] (6.4 ± 3.1 years) and Italy [14] (14.6 ± 1.6 years) were different than our study.
The results from an Omani study [2] revealed a period of illness prior to diagnosis of 4.2 ± 3.2 years, nearer to our observation.Whereas the value from the Thailand study [13] was much lower (6 months).
Our study showed that SLE patients had significantly less weight and height compared to age and sex match controls (Table 7A).We couldn't find any study comparing SLE patients with sex and age matched controls, not even after a thorough literature research.
In our cohort of SLE patients, short stature (height less 2 SD) was found in 38.8% patients.
A study from Bankok [15] by Ponin et al. revealed nearly 25% of children with SLE develop growth impairment.
Research has shown inconsistent results about the severity of growth impairment due to factors such as different definitions of the term, different ages at diagnosis, and different ethnicities of the participants.
In comparison to other research, we discovered that our results were comparable to those of the Pediatric Rheumatology International Trials Organization (PRINTO) [16] longitudinal study.Among boys, 24.5% had growth impairment, while among girls, 14.7% did.
The reason why SLE patients had significantly decreased weights compared to controls but not JIA patients compared to controls are probably due to the following: 1. SLE has multisystem involvement; 2. JIA patients have early detection and treatment; 3. Our SLE patients had delayed treatment compared to JIA, whose mean duration of illness was shorter.
In our study, there was no significant difference in weight, height and BMI parameters among JIA and SLE patients.We didn't find any other study comparing the growth parameters of JIA and SLE.
The reason could be: • both diseases being chronic inflammatory disease; • both requires steroid and immunosuppressive agents; • all SLE and SOJIA varieties (29% of all JIA cohort in our study) have systemic symptoms In our study, 55.5% of the SLE patients (n = 18), were diagnozed with active SLE, while the remaining 44.4% with inactive SLE.The mean SLEDAI score was 9.4 for active patients, and 1 for inactive patients.Overall mean SLEDAI score was 5.6.
The Italy study [14] revealed a mean score of 8 at diagnosis for all SLE patients.
In our study, 34.4% of JIA patients (n = 87) were diagnozed with active JIA, and the remaining 65.5% with inactive JIA.Among active patients, the mean JADAS 10 score was 4.2, among inactive patients, mean JADAS 10 score was 0.5.
In a study from Finland [1], inactive JIA patients had a median score of 0.5.Low disease activity had a median score of 1.6, and the moderate disease activity had a median score of 6.2.
In our study, the incidence of delayed puberty among the two main rheumatic diseases (covering 86.7 % of our cohort of pediatric rheumatic patients) SLE and JIA (Table 9 and Table 10) were 33.3% and 28.7%.
The incidence of delayed puberty in the general population varies in different studies from 2% to 5%.That means that patients with pediatric rheu-matic problems are much more prone to develop delayed puberty.
In our study, delayed puberty was significantly higher in JIA and SLE patients compared to controls (Table 9 and Table 10).
A person's physical development into a sexually mature adult is the consequence of puberty, a crucial life transition characterized by a complicated sequence of hormonal and neurological changes.Researchers have only scratched the surface of the mysteries surrounding the processes that determine when adolescence begins.It is evident, however, that numerous internal and external variables (such as diet, genes, inflammatory condition, endocrine-disruptor drugs, and social changes) can impact the neuroendocrine events that occur during puberty.Adaptive changes, which are both a constraint and an opportunity for healthy growth and development during adolescence, are made possible by the clear plasticity of the timing of puberty and the significance of environmental influences.In children suffering from long-term health conditions, the onset and development of puberty are clear indicators of their emotional and physical well-being.Actually, similar to other inflammatory diseases, pubertal problems are common in children with JIA.This is particularly true in cases when the disease begins before puberty and the chronic inflammatory course is severe and long-lasting (sJIA).The maximum common pubertal abnormality in these patients is delayed puberty, which means that the breasts do not develop or the testicles do not enlarge until a 2-2.5 SD later than the average age of the population.In Western countries, this corresponds to a B2 stage in girls after 13 years of age and a Tanner stage G2 in boys after 14 years.Additionally, there have been reports of sluggish clinical advancement of puberty, isolated delayed menarche in women, and decreased period and intensity of puberty growth [4].
At last, we have noticed that other studies involving growth of pediatric inflammatory arthritis had observed different growth parameters over at diagnosis and follow up or compared the patients with controls.The novelty of our study is that we have compared growth parameters of two common pediatric inflammatory arthritis -JIA and SLE.

Limitations of this study
1.This is a cross sectional study, for a proper evaluation of growth and development, we need to study growth velocity.For this, recording at different stages of the disease is required.
2. A larger population of pediatric rheumatic patients are needed.For this, we will need a longer duration of study.
3. This was a single centered study, a multi centered study is needed to include a large population and cover populations of different areas.

4.
No evaluation was made regarding the severity of growth retardation or its causes or factors affecting any subject or group.

CONCLUSIONS
JIA was most common among patients with inflammatory arthritis attend ing pediatric rheumatol-ogy clinic, followed by SLE.The SOJIA variety was most common among JIA patients.JIA patients had signi ficantly lower height than age and gender matched controls.SOJIA and polyarticular variety had significantly less weight and height than controls.SLE patients had significantly lower weight and height than age and sex matched controls.Delayed puberty was significantly more in both JIA and SLE patients compared to controls.

TABLE 1 .
Incidence of different types of pediatric rheumatic diseases identified FIGURE 1. Incidence of different types of pediatric rheumatic diseases identified MCTD -Mixed Connective Tissue Disease, CRMO -Chronic Recurrent Multifocal Osteomyelitis, PSRA -Post Streptococcal Reactive Arthritis, JDM -Juvenile Dermatomyositis.

TABLE 2 .
Different types of JIA

TABLE 3 .
Age and gender of the patientsTable 3 showes female sex predominance in SLE, and male sex predominance in JIA.Mean age of presentation in JIA is earlier than in SLE.The reason is we had a significant number of SOJIA which has early presentation.

TABLE 4 .
Different types of JIA and mean age of presentation

TABLE 5 .
Duration of illness prior to diagnosis in pediatric rheumatic patients

TABLE 6B .
Mean Z -score of JIA patients

TABLE 7B .
Mean Z -score of SLE patients

TABLE 9 .
Delayed puberty among JIA and controls

TABLE 10 .
Delayed puberty among SLE and controls

TABLE 11 .
Delayed puberty among JIA and SLE patients

TABLE 12 .
p value of JIA patients and controls in different growth parameters -comparison of our studies with other studies