Growth Failure in Children with Systemic Juvenile Idiopathic Arthritis and Prolonged Inflammation despite Treatment with Biologicals: Late Normalization of Height by Combined Hormonal Therapies

Abstract

Background: Biologicals targeting the interleukin (IL)-1β or IL-6 pathway are becoming prime choices for the treatment of children with systemic juvenile idiopathic arthritis (sJIA). Up to 1 in 3 sJIA children receiving such treatment continues to have inflammatory activity and to require supra-physiological glucocorticoid doses which may reduce growth velocity for years and may lead to an extremely short stature for age, if not for life. Currently, there is no long-term proposal to normalize the adult height of these children with sJIA. Methods and Results: We present long-term (up to 10 years), proof-of-concept evidence that the adult stature and adipose body composition of short sJIA children can be normalized with a hormonal combination strategy: (i) pubertal onset is postponed with a gonadotropin-releasing hormone analog (triptorelin) until a minimum height is reached, or until prepubertal growth is exhausted, and (ii) height gain is promoted with growth hormone (≈50 μg/kg/day), once inflammation is under control and high glucocorticoid doses are no longer needed. The latter treatment takes advantage of the window of relative glucocorticoid deficiency, which is known to open after prolonged glucocorticoid administration, and to be uniquely favorable to height gain. Conclusion: A long-term combination of biological and hormonal treatments for short sJIA children can be guided by a simple concept that involves (i) postponement of pubertal development and (ii) growth-promoting therapy after the episodes of major inflammation and high-dose glucocorticoid treatment. Limited long-term experience in short sJIA children suggests that this strategy leads consistently – albeit late – to a normal adult stature.

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway

“…Medical conditions with increased plasma FGF23 levels are related to bone impairment, including X‐linked hypophosphatemia and autosomal dominant hypophosphatemic rickets, which include abnormal bone development, low BMD, growth impairment, and short stature. Also, activation of the FGF23/FGFR3 pathway induced by GCs could also play a role in other medical conditions associated with growth impairment in children such as nephrotic syndrome, inflammatory bowel disease, and autoimmune disorders, where GCs are indicated as short‐ or long‐term therapy.…”

GH therapy in children with juvenile idiopathic arthritis: a four-decade review

“…This is strongly consistent with the recommendation to reduce the height deficit in patients with a short JIA before puberty. A promising therapeutic strategy may consist in delaying pubertal onset with a gonadotropin-releasing hormone analog and promoting growth with high dose of rhGH (0.05 mg/kg/d) when the inflammatory state is lowered, as described in an intriguing study published in 2018 with a long-term follow-up of five extremely short children wit sJIA ( 69 ). A key factor that could make this strategy successful is the use of rhGH in the on-biological phase, once inflammation is controlled and high glucocorticoid doses are no longer required ( 69 ).…”

“…A promising therapeutic strategy may consist in delaying pubertal onset with a gonadotropin-releasing hormone analog and promoting growth with high dose of rhGH (0.05 mg/kg/d) when the inflammatory state is lowered, as described in an intriguing study published in 2018 with a long-term follow-up of five extremely short children wit sJIA ( 69 ). A key factor that could make this strategy successful is the use of rhGH in the on-biological phase, once inflammation is controlled and high glucocorticoid doses are no longer required ( 69 ). In fact, it is known that in patients with JIA, a decrease in glucocorticoid dosage and the introduction of a biologic drug promote a slight increase in height velocity, which is not possible for clear catch-up growth ( 70 , 71 ).…”

Growth and puberty in children with juvenile idiopathic arthritis

“…This fits the suggestion to reduce the height deficit of short JIA patients before the onset of puberty. Some authors presented a long-term evidence (up to 10 years) that the adult height of sJIA patients can be normalized with an hormonal combination strategy, by postponing pubertal onset with a gonadotropin-releasing hormone analog until a more normal late-prepubertal height is reached or until the potential of prepubertal growth is exhausted and then promoting growth with high dose rhGH (0.5 mg/kg/ week on average) when inflammation is reduced and high GCs doses are not needed [92]. In children with JIA, the reduction of GC doses and the initiation of a biological therapy favor an increment in height velocity, which does not evolve in a frank catch-up growth [93,94].…”