Abstract
Introduction:
Children with juvenile idiopathic arthritis (JIA) often have impaired growth and short stature. There is evidence that the therapeutic use of growth hormone (GH) is useful and safe in these patients.
Objective:
To analyze the effects of GH use in patients with JIA.
Method:
A systematic review of the literature over the last 18 years in Medline and Embase databases. The criteria were analyzed independently by the researchers. We used the following keywords: "growth hormone", "arthritis, juvenile", "arthritis, rheumatoid", "child" and "adolescent".
Results:
Among the 192 identified articles, 20 corresponded to the inclusion criteria. Seventeen longitudinal studies and 3 case reports were found. Most studies analyzed observed increased growth, muscle mass and bone mass using GH. Adverse effects observed were glucose intolerance, diabetes, bone deformities, osteonecrosis, reactivation of the disease and low final height.
Conclusion:
The majority of studies reported positive effects after the therapeutic use of GH, but some variability in response to treatment was observed. The combination of growth hormone with other drugs seems to be a good option.
Keywords:
Artrite idiopática juvenil; Hormônio de crescimento; Crianças; Adolescentes
Resumo
Introdução:
Crianças com artrite idiopática juvenil (AIJ) frequentemente apresentam prejuízo no crescimento e baixa estatura. Existem evidências de que o uso terapêutico do hormônio de crescimento (GH) é útil e seguro nesses pacientes.
Objetivo:
Analisar os efeitos do uso de GH em pacientes com AIJ.
Método:
Fez-se revisão sistemática da literatura nos últimos 18 anos, nas bases de dados Medline e Embase. Os critérios foram analisados pelos pesquisadores de forma independente. Usaram-se os seguintes descritores: growth hormone, arthritis, juvenile, arthritis, rheumatoid, child e adolescent.
Resultados:
Entre os 192 artigos identificados, 20 corresponderam aos critérios de inclusão. Foram encontrados 17 estudos longitudinais e três relatos de casos. A maioria dos estudos analisados observou um aumento de crescimento, massa muscular e massa óssea com o uso do GH. Os efeitos adversos observados foram intolerância à glicose, diabetes, deformidades ósseas, osteonecrose, reativação da doença e altura final baixa.
Conclusão:
A maioria dos estudos relatou efeitos positivos após uso terapêutico do GH, porém certa variabilidade na resposta ao tratamento foi observada. A combinação do hormônio de crescimento com outros medicamentos parece ser uma boa opção.
Palavras-chave
Artrite idiopática juvenil; Hormônio de crescimento; Crianças; Adolescentes
Introduction
Juvenile idiopathic arthritis (JIA) is an autoimmune disease and the leading cause of chronic arthritis in pediatric patients. Its annual incidence varies from 2 to 20 cases/100,000 inhabitants, with a prevalence of 15–150 cases/100,000 inhabitants.11 Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint Bone Spine. 2014;81:112-7.
Its main features are chronic arthritis, and in some cases being associated with multisystem involvement and progression to joint limitations and permanent functional disability.22 Tugal-Tutkun I, Quartier P, Bodaghi B. Disease of the year: juvenile idiopathic arthritis-associated uveitis – classification and diagnostic approach. Ocul Immunol Inflamm. 2014;22:56-63.
The diagnosis of JIA is based on criteria of the International League of Associations for Rheumatology (ILAR) and requires the presence of arthritis in children and adolescents aged under 16 years, that persists for at least six weeks, when excluding the presence of other causes of chronic arthritis.33 Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390-2. According to the literature, the most frequent JIA subtypes are oligoarticular JIA (50–60%), polyarticular JIA (30–35%) and systemic JIA (10–20%).44 Petty R, Southwood T, Baum J, Bhettay E, Glass DN, Manners P, et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban 1997. J Rheumatol. 1998;25:1991-4.
Children with JIA often exhibit an inadequate growth and short stature, and these effects relate to the extent of organs involved, with the activity and extent of the disease, malnutrition, malabsorption, increased catabolism, associated complications, a constant inflammatory process, and effects of the use of certain medications, being the most relevant of them the glucocorticoids.55 Simon D, Lucidarme N, Prieur AM, Ruiz JC. Czernichow linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr Endocrinol Metab. 2001;6:1483-6.
6 Macrae VE, Wong SC, Farquharson C, Ahmed SF. Cytokine actions in growth disorders associated with pediatric chronic inflammatory diseases (review). Int J Mol Med. 2006;18:1011-8.
7 von Scheven E, Corbin KJ, Stagi S, Cimaz R. Glucocorticoid-associated osteoporosis in chronic inflammatory diseases: epidemiology, mechanisms, diagnosis, and treatment. Curr Osteoporos Rep. 2014;12:289-99.-88 Stratakis CA. Cortisol and growth hormone: clinical implications of a complex, dynamic relationship. Pediatr Endocrinol Rev. 2006;3:333-8. Several studies have observed improved growth and height rates in patients with JIA treated with growth hormone (GH).55 Simon D, Lucidarme N, Prieur AM, Ruiz JC. Czernichow linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr Endocrinol Metab. 2001;6:1483-6.,99 Kim JY, Kim HS, Park SH. Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander. Int J Rheum. 2015;18:377-8.–2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9. There are several indications of the use of GH approved for treatment of JIA; however, the use of this hormone can result in adverse events,2626 Denson LA. Growth hormone therapy in children and adolescents: pharmacokinetic/pharmacodynamic considerations and emerging indications. Expert Opin Drug Metab Toxicol. 2008;4:1569-80. including negative variability in response to treatment which has been observed in some studies of patients with JIA.99 Kim JY, Kim HS, Park SH. Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander. Int J Rheum. 2015;18:377-8.,1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143.,1414 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2020 Al-Mutair A, Bahabri S, Al-Mayouf S, Al-Ashwal A. Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure. J Pediatr Endocrinol Metab. 2000;13:899-905.,2424 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2727 Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol. 2011;2011:62759.,2828 Bismuth EA, Chevenne DB, Czernichow PA, Simon DA. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465-72.
Due to the high cost and potential side effects,99 Kim JY, Kim HS, Park SH. Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander. Int J Rheum. 2015;18:377-8.,1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143.,2020 Al-Mutair A, Bahabri S, Al-Mayouf S, Al-Ashwal A. Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure. J Pediatr Endocrinol Metab. 2000;13:899-905.,2727 Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol. 2011;2011:62759. there are controversies about the ideal indication, the dose, and duration of the GH therapy in JIA.2626 Denson LA. Growth hormone therapy in children and adolescents: pharmacokinetic/pharmacodynamic considerations and emerging indications. Expert Opin Drug Metab Toxicol. 2008;4:1569-80. An understanding the indications for therapy with growth hormone and its controversies can facilitate the evaluation of the patient and his/her referral to the best treatment.2626 Denson LA. Growth hormone therapy in children and adolescents: pharmacokinetic/pharmacodynamic considerations and emerging indications. Expert Opin Drug Metab Toxicol. 2008;4:1569-80.,2929 Hardin DS, Kemp SF, Allen DB. Twenty years of recombinant human growth hormone in children: relevance to pediatric care providers. Clin Pediatr (Phila). 2007;46:279-86.,3030 De Benedetti F, Brunner H, Ruperto N, Schneider R, Xavier R, Allen R, et al. Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Arthritis Rheumatol. 2015;67:840-8. The aim of this study is to analyze the various effects of GH use in patients with JIA, based on the literature review.
Methods
This study consists of a systematic literature review, after a search conducted during the months of July and August 2015, of studies published in the last 18 years (1998–2015). The search of the references was conducted through an electronic database (Medline and Embase) exploration and of the reference list of identified articles by three researchers independently. References that met the inclusion criteria were evaluated, regardless of their journal. The selection of the descriptors used in the review process was conducted in consultation with DeCS (Health Sciences Descriptors byBIREME). In the search, the following descriptors in Portuguese and English were considered: "growth hormone", "arthritis, juvenile", "arthritis, rheumatoid," "child" and "adolescent".3131 Harris JD, Quatman CE, Manring MM, Siston RA, Flanigan DC. How to write a systematic review. Am J Sports Med. 2014;42:2761.
In the electronic database MedLine, 104 studies were identified, and Embase 88 studies were identified, totaling 192 studies. 64 matching studies were identified, and 128 articles were tabulated on a spreadsheet with data related to the title of the study, journal, year, age group studied, study idiom, evaluated diseases, disease duration, treatment time, therapeutic dose, and possible use of growth hormone as a therapy.
The inclusion criteria were as follows: (1) Original articles; (2) Articles in Portuguese or in English idiom; (3) Articles which used growth hormone as a therapy; (4) Articles that evaluated patients with JIA; (5) Articles that included children and adolescents in their sample (Fig. 1).
Results
Twenty studies were included, of which 17 had longitudinal design55 Simon D, Lucidarme N, Prieur AM, Ruiz JC. Czernichow linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr Endocrinol Metab. 2001;6:1483-6.,1111 Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.
12 Bechtold S, Ripperger P, Dalla PR, Roth J, Hafner R, Michels H, et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab. 2010;95:178-85.
13 Bechtold S, Ripperger P, Dalla PR, Bonfig W, Hafneer R, Michels H. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007;92:3013-8.
14 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.
15 Bechtold S, Ripperger P, Bonfig W, Pozza RD, Haefner R, Schwarz HP. Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:3168-73.
16 Saha MT, Haapasaari J, Hannula S, Sarna S, Lenko HL. Growth hormone is effective in the treatment of severe growth retardation in children with juvenile chronic arthritis. Double blind placebo-controlled followup study. J Rheumatol. 2004;31:1413-7.
17 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.
18 Bechtold S, Ripperger P, Häfner R, Said E, Schwarz HP. Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study. J Pediatr. 2003;143:512-9.
19 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.
20 Al-Mutair A, Bahabri S, Al-Mayouf S, Al-Ashwal A. Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure. J Pediatr Endocrinol Metab. 2000;13:899-905.
21 Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.
22 Rooney M, Davies UM, Reeve J, Preece M, Ansell BM, Woo PM. Bone mineral content and bone mineral metabolism: changes after growth hormone treatment in juvenile chronic arthritis. J Rheumatol. 2000;27:1073-81.
23 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6.
24 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.-2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2828 Bismuth EA, Chevenne DB, Czernichow PA, Simon DA. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465-72. and three were case reports.99 Kim JY, Kim HS, Park SH. Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander. Int J Rheum. 2015;18:377-8.,1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143.,2727 Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol. 2011;2011:62759. A total of 359 patients with JIA (systemic, polyarticular, and oligoarticular) were treated with GH, with doses ranging from 0.028 to 0.067 mg/kg/day, and aged from 4 to 17 years; the treatment time ranged from 9 months to 6 years (Tables 1 and 2).
Description of articles on Growth Hormone (GH) effects in patients with Juvenile Idiopathic Arthritis (JIA) (longitudinal studies): 1998-2015.
Description of articles on Growth Hormone (GH) effects in patients with Juvenile Idiopathic Arthritis (JIA) (case reports): 1998-2015.
After use of GH, an increased growth of JIA patients was demonstrated in 80% of the studies,55 Simon D, Lucidarme N, Prieur AM, Ruiz JC. Czernichow linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr Endocrinol Metab. 2001;6:1483-6.,1111 Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.–2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9. and 35% reported significant improvement in pubertal development.1111 Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.–1313 Bechtold S, Ripperger P, Dalla PR, Bonfig W, Hafneer R, Michels H. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007;92:3013-8.,1616 Saha MT, Haapasaari J, Hannula S, Sarna S, Lenko HL. Growth hormone is effective in the treatment of severe growth retardation in children with juvenile chronic arthritis. Double blind placebo-controlled followup study. J Rheumatol. 2004;31:1413-7.,1717 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.,2424 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.
Among the positive effects of the treatment, 30% of the studies reported improvement in bone mineral density and bone metabolism.1212 Bechtold S, Ripperger P, Dalla PR, Roth J, Hafner R, Michels H, et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab. 2010;95:178-85.,1717 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2121 Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.,2323 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6. In comparison with pre-treatment values, it was reported that the formation and resorption markers increased significantly during treatment,1717 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.,2121 Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.,2323 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6. and that the plasma level of osteocalcin was the best variable predictive of growth in JIA patients who had been treated with GH.2121 Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.
One study found that the fat level has remained stable, with no significant changes versus patients who did not use GH;1212 Bechtold S, Ripperger P, Dalla PR, Roth J, Hafner R, Michels H, et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab. 2010;95:178-85. but in 4 (20%) studies, lean mass increase and fat mass decrease were observed.1515 Bechtold S, Ripperger P, Bonfig W, Pozza RD, Haefner R, Schwarz HP. Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:3168-73.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2323 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.
Regarding blood glucose and glucose intolerance in 5 (25%) studies,1414 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2424 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2828 Bismuth EA, Chevenne DB, Czernichow PA, Simon DA. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465-72. a significant increase in fasting blood glucose was noted in patients treated with GH versus control group, which led, in some cases, to the possible development of insulin resistance,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2424 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2828 Bismuth EA, Chevenne DB, Czernichow PA, Simon DA. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465-72. and to diabetes.2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2828 Bismuth EA, Chevenne DB, Czernichow PA, Simon DA. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465-72. Increases in glycosylated hemoglobin were also described.1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2424 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.
Development of osteonecrosis1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143. was observed in one case report; in another report, one patient developed severe deformity in both knees.2020 Al-Mutair A, Bahabri S, Al-Mayouf S, Al-Ashwal A. Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure. J Pediatr Endocrinol Metab. 2000;13:899-905. In case reports, reactivation of the disease in two studies99 Kim JY, Kim HS, Park SH. Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander. Int J Rheum. 2015;18:377-8.,1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143. and low final height in one study were observed.2727 Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol. 2011;2011:62759.
Discussion
Recombinant GH has revolutionized the treatment of children and adolescents with growth hormone deficiency and other growth disorders, but the clinical and ethical controversies remain, about the diagnostic approach in patients with JIA, as well as the optimal dose, duration, and expected results.1111 Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.,1212 Bechtold S, Ripperger P, Dalla PR, Roth J, Hafner R, Michels H, et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab. 2010;95:178-85.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2626 Denson LA. Growth hormone therapy in children and adolescents: pharmacokinetic/pharmacodynamic considerations and emerging indications. Expert Opin Drug Metab Toxicol. 2008;4:1569-80.
The results obtained by many longitudinal studies confirmed previously published data, that the treatment with GH of patients with JIA allows positively affect the pubertal development and final height.55 Simon D, Lucidarme N, Prieur AM, Ruiz JC. Czernichow linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr Endocrinol Metab. 2001;6:1483-6.,1111 Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.–2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.
It is known that the treatment instituted, particularly the use of glucocorticoids, also compromise the growth, which depends on other factors such as age of onset of the disease, its severity, the patient's response to treatment, time of administration, and dose of the glucocorticoid administered.88 Stratakis CA. Cortisol and growth hormone: clinical implications of a complex, dynamic relationship. Pediatr Endocrinol Rev. 2006;3:333-8.
Bone formation and resorption markers increased significantly during the treatment with GH1414 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.,1717 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2121 Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.–2323 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6.; but a study observed loss of growth following the discontinuation of the treatment.2323 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6. It is believed that a prolonged treatment with GH is needed, in order to allow an assessment of a positive effect of this hormone on the bone density and metabolism in patients with JIA.1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143.,1414 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.,1717 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2323 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9. The monitoring of patients to their final height, besides bone mass evaluation, are needed to better understand the potential beneficial effect of GH treatment.55 Simon D, Lucidarme N, Prieur AM, Ruiz JC. Czernichow linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr Endocrinol Metab. 2001;6:1483-6.,1111 Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.
12 Bechtold S, Ripperger P, Dalla PR, Roth J, Hafner R, Michels H, et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab. 2010;95:178-85.
13 Bechtold S, Ripperger P, Dalla PR, Bonfig W, Hafneer R, Michels H. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007;92:3013-8.
14 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.
15 Bechtold S, Ripperger P, Bonfig W, Pozza RD, Haefner R, Schwarz HP. Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:3168-73.
16 Saha MT, Haapasaari J, Hannula S, Sarna S, Lenko HL. Growth hormone is effective in the treatment of severe growth retardation in children with juvenile chronic arthritis. Double blind placebo-controlled followup study. J Rheumatol. 2004;31:1413-7.
17 Bechtold S, Ripperger P, Bonfig W, Schmidt H, Bitterling H, Hafner R, et al. Bone mass development and bone metabolism in juvenile idiopathic arthritis. J Rheumatol. 2004;31:1407-12.
18 Bechtold S, Ripperger P, Häfner R, Said E, Schwarz HP. Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study. J Pediatr. 2003;143:512-9.
19 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.
20 Al-Mutair A, Bahabri S, Al-Mayouf S, Al-Ashwal A. Efficacy of recombinant human growth hormone in children with juvenile rheumatoid arthritis and growth failure. J Pediatr Endocrinol Metab. 2000;13:899-905.
21 Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.
22 Rooney M, Davies UM, Reeve J, Preece M, Ansell BM, Woo PM. Bone mineral content and bone mineral metabolism: changes after growth hormone treatment in juvenile chronic arthritis. J Rheumatol. 2000;27:1073-81.
23 Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6.
24 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.-2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2727 Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol. 2011;2011:62759.
As to glucose intolerance, studies did not find patients with abnormal glucose metabolism symptoms before use of GH.1414 Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.,1919 Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czernichow P. Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol. 2003;30:2492-9.,2424 Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.,2828 Bismuth EA, Chevenne DB, Czernichow PA, Simon DA. Moderate deterioration in glucose tolerance during high-dose growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465-72. The metabolism of carbohydrates must be carefully monitored in JIA patients treated with GH, particularly during the acute phase of their disease. It is known that glucocorticoids interfere with the GH/IGF-1 axis, decreasing the GH pulsatile secretion by increasing of somatostatin levels and that these pharmaceuticals also reduce the expression of GH receptors on hepatocytes, causing some degree of resistance to GH, with a consequent reduction of IGF-1 levels.3232 Zak M, Muller J, Karup PF. Final height, armspan, subischial leg length, and body proportions in juvenile chronic arthritis. A long-term follow-up study. Horm Res. 1999;52:80-5.,3333 Stratakis CA. Cortisol and growth hormone: clinical implications of a complex, dynamic relationship. Pediatr Endocrinol Ver. 2006;2:333-8.
Theoretically, GH not only regulates growth but also controls the immune function, considering that it is not common an occurrence of relapse of disease activity after several years of remission without a definite cause.1818 Bechtold S, Ripperger P, Häfner R, Said E, Schwarz HP. Growth hormone improves height in patients with juvenile idiopathic arthritis: 4-year data of a controlled study. J Pediatr. 2003;143:512-9.,2525 Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9. It has been questioned if GH was responsible for the reactivation of the disease in those case reports presented in this paper.99 Kim JY, Kim HS, Park SH. Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander. Int J Rheum. 2015;18:377-8.,1010 Nikishina IP, Rodionovskaya SR, Shapovalenko AN, Filippova LY, Jostareva OM. An experience of sequental use of three biologics and recombinant growth hormone in a patient with juvenile idiopathic arthritis associated with unsuccessful outcome of hip damage. Pediatr Rheumatol. 2011;9:143.
One study reported an atypical case of JIA, with short stature after the use of GH; however, this result cannot be generalized to other studies because the patient suffered from other concomitant diseases.2727 Pun T, Chandurkar V. Growth hormone deficiency, short stature, and juvenile rheumatoid arthritis in a patient with autoimmune polyglandular syndrome type 1: case report and brief review of the literature. ISRN Endocrinol. 2011;2011:62759.
It should be stressed that JIA is a disease with multiple clinical manifestations among affected individuals (a systemic, polyarticular, oligoarticular, etc., onset). Thus, there are no double-blind randomized controlled studies or trials with placebo versus the use of GH. A better understanding of the disease and more effective treatments in recent years can radically change the growth status of these patients. Some authors suggest that the treatment with GH is implemented in combination with other drugs, and biological drugs are among those most favored.3030 De Benedetti F, Brunner H, Ruperto N, Schneider R, Xavier R, Allen R, et al. Paediatric Rheumatology International Trials Organisation and the Pediatric Rheumatology Collaborative Study Group. Arthritis Rheumatol. 2015;67:840-8.
Conclusion
The studies published in recent years show improved growth and height rates in JIA patients treated with GH.
Some variation in the response to treatment was observed; in some cases, recovery in growth takes place, and in other cases the treatment prevents the loss of height generally observed during the natural course of the disease. The selection of the response depends on the initiation of treatment with GH and the on disease severity and activity. The studies presented in this review are singular, concerning the studied factors (positive and negative effects) and cannot be generalized. The combination of growth hormone with other drugs may be an option.
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FundingSimone Appenzeller CNPq (304255/2015-7).
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Erratum
On article "Effects of the use of growth hormone in children and adolescents with juvenile idiopathic arthritis: a systematic review" [Rev Bras Reumatol. 2017;57(2):100-106], where it reads:Barbara Sugui Longuiit should readBarbara Sugui Longhi
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11Bechtold S, Beyerlein A, Ripperger P, Roeb J, Dalla PR, Hafner R, et al. Total pubertal growth in patients with juvenile idiopathic arthritis treated with growth hormone: analysis of a single center. Growth Horm IGF Res. 2012;22:180-5.
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12Bechtold S, Ripperger P, Dalla PR, Roth J, Hafner R, Michels H, et al. Dynamics of body composition and bone in patients with juvenile idiopathic arthritis treated with growth hormone. J Clin Endocrinol Metab. 2010;95:178-85.
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14Simon D, Prieur AM, Quartier P, Charles Ruiz J, Czernichow P. Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: a 3-year randomized study. J Clin Endocrinol Metab. 2007;92:2567-73.
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16Saha MT, Haapasaari J, Hannula S, Sarna S, Lenko HL. Growth hormone is effective in the treatment of severe growth retardation in children with juvenile chronic arthritis. Double blind placebo-controlled followup study. J Rheumatol. 2004;31:1413-7.
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-
21Touati G, Ruiz JC, Porquet D, Kindermans C, Prieur AM, Czernichow P. Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy. J Rheumatol. 2000;27:1287-93.
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22Rooney M, Davies UM, Reeve J, Preece M, Ansell BM, Woo PM. Bone mineral content and bone mineral metabolism: changes after growth hormone treatment in juvenile chronic arthritis. J Rheumatol. 2000;27:1073-81.
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23Simon D, Prieur A, Czernichow P. Treatment of juvenile rheumatoid arthritis with growth hormone. Horm Res. 2000;53:82-6.
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24Simon D, Touati G, Prieur AM, Ruiz JC, Czernichow P. Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis. Acta Paediatr Suppl. 1999;88:100-5.
-
25Touati G, Prieur AM, Ruiz JC, Noel M, Czernichow P. Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition. J Clin Endocrinol Metab. 1998;83:403-9.
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Publication Dates
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Publication in this collection
Mar-Apr 2017
History
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Received
23 Nov 2015 -
Accepted
07 Apr 2016