|Ahead of print publication
Growth and development in children with rheumatic diseases: Maintaining a balance between drugs and disease activity
Sagar Bhattad, Rachna Shanbhag Mohite, Neha Singh
Department of Pediatrics, Pediatric Immunology and Rheumatology Unit, Aster CMI Hospital, Bangalore, Karnataka, India
|Date of Submission||15-Mar-2022|
|Date of Acceptance||04-Sep-2022|
|Date of Web Publication||07-Oct-2022|
Department of Pediatrics, Pediatric Immunology and Rheumatology Unit, Aster CMI Hospital, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Rheumatic diseases are autoimmune disorders that affect the bones, skin, and muscles, and they contribute to a significant burden of chronic illnesses in children throughout the world, the most common of them being juvenile idiopathic arthritis (JIA). Symptoms begin at a young age and last throughout maximum growth potential in these children. Long-term consequences usually follow delayed diagnosis and contribute to increasing disease burden, joint damage, deformity, and delayed growth and development. Children with systemic arthritis with uncontrolled disease, and/or prolonged use of corticosteroids have an increased risk of growth impairment. Uveitis associated with JIA has a significant impact on academic competence and social development. On the other hand, newer diseases such as autoinflammatory diseases not only pose a challenge in diagnosis but also in management due to the lack of easy availability of targeted therapy. Rheumatic disease in adolescents has more pronounced effects on the development of self-identity, self-confidence, and sexual development. Therefore, there is a need to establish psychosocial and educational interventions targeted at improving social support, resolving insecurities, and building confidence among these adolescents. Drugs used in the treatment of rheumatic illnesses such as glucocorticoids, disease modifying anti-rheumatic drugs (DMARDs), and biologics have both short-term and long-term effects on growth and overall development. A treat-to-target approach and use of various disease activity monitoring tools are efforts in the direction of standardizing treatment and achieving and maintaining prolonged disease remission. Finally in order to provide a holistic care, we need to ease the access to pediatric rheumatologists, increase the awareness of these diseases among the medical fraternity and community, build financial and social systems to support both patients and their families. In this article, we highlight the various aspects of rheumatic diseases in childhood and their possible effects on the overall growth and development in children.
Keywords: Development, growth, juvenile idiopathic arthritis, pediatric rheumatic disease, systemic lupus erythematosus
|How to cite this URL:|
Bhattad S, Mohite RS, Singh N. Growth and development in children with rheumatic diseases: Maintaining a balance between drugs and disease activity. Indian J Rheumatol [Epub ahead of print] [cited 2023 Jan 30]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=358025
| Introduction|| |
The 19th century was a landmark in the history of pediatric rheumatology when the study of children with rheumatic diseases began. Initially, the center of attention was rheumatic fever, and it was only in the 1940s that other rheumatic diseases began to receive some attention. Rheumatic diseases are autoimmune disorders that affect the bones, skin, and muscles, and they contribute to a significant burden of chronic illnesses in children worldwide, the most common being juvenile idiopathic arthritis (JIA). The prevalence of childhood rheumatic diseases varies across different geographic regions of the world. The prevalence of systemic lupus erythematosus (SLE) is 0.4–0.6/100,000 children to JIA, ranging from 0.07 to 10/100,000 children., Chronic rheumatic diseases are known to have a significant impact on growth and development in children.
| Impact of Rheumatic Diseases on Growth and Development|| |
Rheumatic diseases such as JIA often begin at a very young age. The most common age of the first presentation ranges between 4 months to 14 years. The mean age of disease onset was reported to be 7 ± 5.7 years in the US, 9.29 + 4.53 years in Singapore, and 14 years in Nigeria. However, due to lack of awareness, delay in referral, and unavailability of a Pediatric Rheumatologist, these diseases often remain undiagnosed.
The delay in diagnosis is a problem faced by both developed and developing countries. Rodriguez et al. reported a delayed diagnosis in pediatric patients in the USA, where there are about 300 certified pediatric rheumatologists. Similarly, in the UK cohort, a significant delay in diagnosis was attributed to the time taken to reach the clinic after complex pathways. Long-term consequences usually follow delayed diagnosis and contribute to increasing disease burden, joint damage, deformity, and delayed growth and development.
In a study involving 1147 Canadian children, newly diagnosed patients with JIA were followed up for a median of 35.5 months. Their weight and height were measured every 6 months for 2 years, then yearly up to 5 years. Most children in this modern JIA cohort gained weight and height as normally as children in the general population. The estimated incidence of growth delay within 3 years of diagnosis for the whole cohort was 8.5% and it varied from 5.7% to 9.9% across JIA categories except for systemic arthritis, where it was much higher (22.5%). One in 10 children who had systemic arthritis with uncontrolled disease, and or prolonged use of corticosteroids had an increased risk of growth impairment.
Children with JIA are at increased risk of developing chronic uveitis. Uveitis occurs in approximately 1 in 10 patients with JIA. Chronic uveitis poses a significant financial and emotional burden on children and their families. Other issues that often remain unaddressed include psychological stress due to frequent hospital visits and discomfort associated with daily topical eye drops and injectable medicines. Children with uveitis-related poor visual acuity may struggle with the day-to-day functioning at school, including difficulty in seeing the board in class, reading, writing, and independently completing homework significantly affecting their academic competence. Children also report difficulty in their ability to play and interact with peers, whereas adolescents may experience embarrassment related to the need for eye surgery. Complications such as cataracts, glaucoma, macular edema, and visual handicap can have long-standing effects on adulthood.
Another common childhood rheumatic illness is pediatric SLE which accounts for 10%–20% of all SLE cases. Pediatric SLE is associated with higher disease severity, higher frequency of renal involvement, more frequent use of immunosuppressive therapies and more rapid development of damage. Damage accrual is maximum during the first 5–10 years of the disease onset, which is also the time of maximum growth potential and puberty in children. As a result, these children suffer from growth impairment and delayed puberty. Growth impairment was seen in 23.6% of patients (17.2% in girls and 52.6% in boys) with childhood-onset SLE. Male sex, cumulative corticosteroid dose (prednisolone equivalent) >230 mg/kg received before the late phase of puberty, duration of disease before menarche in girls, and appearance of adult voice in boys were some of the predictors of growth impairment. Failure to develop adequate peak bone mass during adolescence was associated with an increased risk of early osteoporosis and fractures. A longitudinal PRINTO study on growth and puberty in childhood SLE reported an increased reduction in parent-adjusted height Z score in both males and females. Increase in median body mass index (BMI) Z score peaked at 6 months and remained above baseline after 26 months. Delayed onset of puberty was seen in 15.3% and 24% of the females and males, respectively.
Localized scleroderma being more common in children than in adults, complications such as limb asymmetry, contractures, and psychosocial disability associated with localized scleroderma lead to significant impairment in growth and development. Therefore it is essential to control the disease activity and maintain the disease in remission. Juvenile dermatomyositis (JDM) is another chronic illness that has a significant impact on the growth of affected children. A multinational study was carried out to assess the growth parameters and puberty in children with JDM. Growth failure was seen in 21% of female and 15% of male patients, whereas delayed puberty was noted in 36.4% of female and 35.5% of male patients. The highest risk of growth failure was noted in children in the early pubertal stage at baseline.
Amyloidosis is a known complication of chronic inflammatory disorders such as JIA. In a large series of 3500 children with JIA, 24 children developed amyloidosis contributing to death in 42% of affected patients. Mortality was higher in patients treated with prednisolone alone. Patients who received disease-modifying drugs had better outcomes and all live patients had completed at least 9 years of compulsory education, and four had completed academic degrees. In today's era of modern medicine, the increasing use of disease-modifying drugs has significantly modified the course and improved outcomes in children. As a result, amyloidosis is sparingly noted in children with JIA.
| Adolescents with Rheumatic Diseases have Unique Challenges|| |
The transition from adolescence to adulthood is a period of physical, social, and emotional evolution. This transition can be challenging, especially in children suffering from chronic rheumatic illnesses. Hence, it is important to recognize the psychosocial and social impact of these diseases on adolescents and young adults. The major difference between adults with rheumatoid arthritis and JIA is the lack of fully developed coping mechanisms in childhood and adolescence. Hence, they are at an increased risk of anxiety and depression. David et al. reported clinical depression in 21% of adults with polyarticular JIA with a correlation with the degree of disability. Depression was most commonly seen in children with onset of JIA between 6 and 12 years (11.2%) as compared to 2.7% in early and 0% in late-onset JIA. Patients with late onset (over 12 years of age) had the highest risk (41.5%) of anxiety-related problems compared to mid- and early-onset JIA patients. The lack of sufficient cognitive development to understand the effects of the disease proved to be beneficial in the early onset group, whereas the mid and late-onset groups had a more pronounced effect on the development of self-identity and self-confidence.,
Pain, functional restriction, joint deformities, and changes in facial appearance, such as hirsutism and acne due to steroid exposure, can lead to poor body image in adolescents. This can affect the ability of an individual to participate in social activities. Such individuals struggle to develop healthy social and sexual relationships. Disturbed family environments and the attitudes of peers can negatively affect the transition from adolescence to adulthood. Eccleston et al. reported that adolescents with chronic pain judged themselves to be less developed than their peers. Positive peer relations had a protective role in psychosocial development.
Tunnicliffe et al. studied the experiences and perspectives of adolescents and young adults diagnosed with SLE. Adolescents with SLE perceived that they had limited physical and social capacities and restricted career and personal goals. There is a need to establish psychosocial and educational interventions targeted at improving social support, resolving insecurities, and building confidence among these adolescents.
| How do Medications affect Growth and Development?|| |
Various medications are used to treat childhood rheumatic illnesses, such as glucocorticoids, disease-modifying agents and biologics. Although these drugs are a boon for Pediatric Rheumatologists involved in treating these children, each of these drugs is associated with many possible side effects. Growth impairment was reported in a cohort of newly diagnosed JIA on 1 mg/kg/day of prednisolone equivalents maintained for a duration of 6 months. A decrease of 0.64 in height Z scores (0.56–0.82) and an increase of 0.74 in BMI Z-scores (0.56–0.92) was reported. The incidence of short stature (6.6%) and obesity (25%) among prolonged corticosteroid users within 3 years was high as compared to nonusers (short stature 2.6%, obesity 8.5%). Higher disease burden was associated with lower height Z-scores, but the impact was minor, relative to that of corticosteroids. A similar impact on BMI has been shown in children with a variety of rheumatic diseases on corticosteroid treatment. In children starting moderate and high dose glucocorticoids, BMI Z scores peaked at 4 months and returned to within +0.25 standard deviation of their baseline BMI Z score in only half of them after 18 months. Another study from Israel reported 95 children with oligoarticular JIA, and after a mean follow-up of 6 years, 11.6% of children reported severe growth retardation.
Rygg et al. reported that one of the determinants of growth failure in patients with pediatric SLE was a cumulative steroid dose >400 mg/kg. Chédeville et al. studied the changes in growth parameters associated with the response to methotrexate (MTX) therapy in prepubertal children with JIA who had not been treated with steroids. Children who responded to MTX therapy had a significant increase in growth parameters.
Cyclophosphamide (CYC) is an alkylating agent commonly used in the treatment of SLE nephritis and other vasculitis. CYC is known to affect the rapidly dividing cells such as the ovarian follicles, hence predisposing these young girls to premature ovarian failure. Boumpas et al. reported that patients with lupus who were treated with CYC developed sustained amenorrhea (>12 months). This was more commonly noted in children who received 15 doses compared to those receiving seven doses of CYC. Another study observed that female lupus patients previously treated with CYC had higher rates of transient amenorrhea and early menopause than those who were not. A group of patients with SLE with normal cervical cytology at baseline were followed up for 3 years. The incidence of cervical intraepithelial neoplasia (CIN) was 15% among patients who were exposed to CYC as compared to no new cases of CIN in subjects exposed only to prednisolone or azathioprine.
A study by Giannini et al. evaluated the effect of long-term etanercept treatment, with or without MTX, on growth in children with selected categories of JIA. Statistically significant increases in the mean height percentiles from baseline were observed in the etanercept treated patients at 3 years and in patients treated with etanercept plus MTX at 1, 2, and 3 years.
Recent advances in the treatment of rheumatic diseases mitigate growth impairments in children. This may be due to the ability to achieve early and better control of disease activity, use of low-dose glucocorticoids or a combination of both. The recent update of the American College of Rheumatology on the treatment of systemic arthritis recommends initial monotherapy with biologics as a treatment option. With the increasing use of biologics, we may be able to decrease steroid exposure in young children, thereby preventing growth impairments.
| Treat to Target|| |
The concept of treat-to-target, (T2T) has been applied to several diseases such as diabetes, hypertension, and rheumatoid arthritis and has been known to improve outcomes for patients. The T2T strategy comprises four key steps, which include establishing an individualized target, taking steps to achieve it, monitoring the target achievement, and adjustment of therapy if the target is not achieved. This approach is now being increasingly applied to treat rheumatic diseases such as JIA and SLE. The T2T approach in patients with polyarticular JIA defined the treatment target endpoints after 3, 6, 9, and 12 months after starting treatment. On T2T guidance, significantly more patients reached juvenile arthritis disease activity score (JADAS) remission and JADAS-Minimal disease activity (JADAS) after 12 months. About half of the patients reached their therapeutic goals without a biologic.
Over the past few years, efforts have been made to better define terms such as “Disease activity,” “Disease severity,” and “Disease damage” in order to objectively document and monitor disease in pediatric rheumatic illnesses. International collaborative efforts over the past few years have made it possible to validate tools to measure disease activity, treatment response, inactive disease, and flare of the disease. The JADAS is a measure of absolute disease activity in JIA, whereas the SLE Disease Activity Index is used in patients with SLE and childhood myositis activity score and manual muscle testing 8 in children with JDM. Swart et al. assessed if the JADAS71 could be used to correctly identify patients with oligoarticular and polyarticular JIA in need of anti-tumor necrosis factor therapy (anti-TNF) therapy 3 and 6 months after the start of MTX. Physicians escalated therapy in patients with higher physician global assessment, visual analog scale, and clinical JADAS, and a decision not to escalate was optimum in 70%–75% of cases who had responded to MTX. The study concluded that the JADAS score is a user-friendly tool to assess the need to escalate to anti-TNF therapy in these patients. Pediatric rheumatic diseases are multidimensional; hence, it is important to assess the disease in several domains. These tools are designed to assess not only the physician's perspective of the disease but also include patient and parent-reported outcomes. This is a welcome step toward a holistic approach in treating these diseases. However, there are several challenges in using these disease monitoring scales on a day-to-day basis. Time being crucial in a busy OPD practice, it is often cumbersome and time-consuming to meticulously perform these assessments.
| Precision Medicine-are we There?|| |
The 'one size fits all' approach does not hold well in Pediatric Rheumatology practice. Although most patients respond to the conventional treatment, however, a small subset fails to respond, requiring a change of therapy. The lack of biomarkers to guide therapy at the outset and personalize treatment is a major challenge faced by rheumatologists. Precision medicine seems a far-fetched goal in today's practice, and there is a definite need to encourage more research toward achieving it.
| Long-Term Outlook|| |
Early diagnosis, timely treatment, and increasing use of DMARDs and biologics over the past few decades have significantly improved outcomes in patients with pediatric rheumatic diseases. This has caused a shift in focus from short-term morbidity and mortality to long-term outcomes in these patients. A mortality of 12% was reported in patients with child-onset SLE during a 5-year follow-up period with a median age of death of 33 years. Childhood-onset SLE was found to be a strong predictor of mortality in this cohort which included both childhood-onset and adult-onset SLE. Lymphopenia and nephrotic range proteinuria were identified as risk factors for early-onset cardiovascular disease in pediatric SLE., Similarly, in patients with JIA, bone mineral density was higher in patients with inactive disease versus those with active disease. Several studies have reported that patients with JIA, JDM, or childhood-onset SLE are at an increased risk for decreased reproductive health as a result of ongoing chronic inflammatory states or medications used for treatment.,,
Minden et al. reported long-term JIA outcomes in 33 patients with HLA B27 positive enthesitis-related arthritis who were assessed at a median of 11 years. Eighteen percent of patients were in remission, 76% reported recurrent back pain, 39% had definite ankylosing spondylitis, and 24% developed uveitis during the disease course. These studies emphasize the need to establish mechanisms to objectively document and assess the adult outcomes and long-term quality of life of patients with childhood-onset rheumatic diseases.
Although there exists enormous data on the treatment options and guidelines in these children, there still remains a paucity of data on the de-escalation of therapy in patients who achieve remission. Optimizing therapy and establishing guidelines on de-escalation of therapy shall help in defining the duration of treatment, decreasing exposure and side-effects of medications, thereby decreasing the long-term effects on growth and development in these children.
| Transition from Pediatric to Adult Caregivers|| |
The transition of care of adolescents from pediatric to adult rheumatologists must involve providing adequate support, advice, and interventions to help individuals reach their optimum potential as an adult. During the transition period, it is important to achieve adequate disease control, minimize physical disability and ensure social, developmental, and vocational needs are addressed. The aim of a successful transition process must provide coordinated and uninterrupted healthcare, promote skills in decision-making, communication, and enhance a sense of control of and independence from healthcare. It is also important to address other generic issues such as alcohol and drug misuse, and sex education as a part of adolescent health service.
| Need for a Holistic Approach|| |
Many children with childhood-onset rheumatic disease will continue to have ongoing disease activity or experience sequelae in adulthood. Several factors affect the growth and development in children with rheumatic illnesses [Figure 1]. Over the past few decades, though there is increasing awareness and recognition of rheumatic illness in the pediatric population, several challenges exist in the Indian settings. There exists a gross lack of understanding and denial of the severity of these diseases among parents and the community at large assorting to alternative forms of medicine increasing the likelihood of long-term complications and poor outcomes in children. Access to pediatric rheumatology services is still poor as compared to adult services. Therefore, we need many more trained pediatric rheumatologists to cater to the needs of society. In the meantime, to bridge this gap, primary care physicians must be trained in diagnosis, initial management, and timely referral to specialists. We need collaborative efforts from the government, physicians and pharmaceutical companies in improving the availability of drugs such as disease-modifying agents and biologics. Chronic rheumatic diseases are not limited to the child but have an impact on the family as a whole. Financial and social strains imposed on the families of these patients often lead to discontinuation of treatment. This has a great impact on the child's functional capacities and abilities to contribute to society and the country at large. Therefore, to provide holistic care, there is a dire need to build better support systems for both patients and their families.
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Conflicts of interest
There are no conflicts of interest.
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