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Endocrine Care |
Endocrine Division University Children’s Hospital, D-80337 Munich, Germany; Children’s Clinic for Rheumatology (P.R., H.T., R.H.), 82467 Garmisch-Partenkirchen, Germany; and Department of Clinical Chemistry, University Clinic Grosshadern (D.M.), 81377 Munich, Germany
Address all correspondence and requests for reprints to: Dr. S. Bechtold, Kinderklinik und Kinderpoliklinik, im Dr. von Haunerschen Kinderpital, Pädiatrische Endokrinologie, Lindwurmstrasse 4, D-80337 Munich, Germany. E-mail: susanne.bechtold{at}kk-i.med.uni-muenchen.de
Abstract
Disturbance of growth frequently occurs in children suffering from juvenile chronic arthritis (JCA). Recognition of growth impairment is important because reduced final height is one of the permanent consequences. The aim of this study was to evaluate the efficacy and safety of human GH (hGH) in growth-retarded prepubertal children with JCA. Thirty-five children were tested for GH deficiency (GHD) and randomly assigned to a study and an untreated control group; five were GH deficient and were part of the GHD group. All received glucocorticoids. The study group was treated with 1 IU/kg BW·wk hGH; the GHD group was given 0.5 IU. During 2 yr of hGH treatment growth velocity and height SD score increased compared with baseline values. There was a marked increase in growth velocity in the treated groups, but also some increase in the control group. Plasma levels of IGF-I and IGF-binding protein-3 increased with GH treatment.
These results suggest that hGH might be useful in the treatment of growth impairment in JCA. GH may counteract the adverse effects of glucocorticoid therapy, but its effect is dependent on the disease activity. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in JCA.
DISTURBANCE OF GROWTH is well recognized in chronic diseases. Growth retardation is a serious problem in juvenile chronic arthritis (JCA). Still (1) noted a general arrest of growth when the disease began in early childhood. The potential for disturbance of linear growth is greatest in children with active systemic disease of long duration (2, 3). The precise etiology of growth retardation is unknown; however, multiple factors have been implicated. Of particular importance are disease activity and drugs such as glucocorticoids (GC), which are often necessary (4). Kienböck (5) described growth retardation in JCA at a time when GC were not yet available for therapy of this disease. Nevertheless, GC are known to play an important role, with catabolic effects and disturbance of GH secretion and action (6, 7, 8). Numerous investigations of GH concentration and secretion have been performed in patients with different chronic diseases, including JCA during long-term GC therapy, with quite controversial results (9, 10, 11, 12). Low concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3) have been documented in JCA (13, 14, 15).
Recognition of growth impairment is important, because reduced final height is one of the permanent sequelae. Osteopenia and associated fractures are further complications in these children (16, 17, 18). Increased growth velocity has been reported in some JCA patients during GH treatment. Several uncontrolled studies of GH treatment in JCA have been published; most were performed with a limited number of patients (19, 20, 21, 22, 23).
The aim of our controlled study was to evaluate the efficacy and safety of GH in JCA. We summarize our data of a 2-yr course of GH treatment on growth and bone in 19 prepubertal children in comparison to 16 untreated prepubertal controls. All children suffered from JCA and had an impaired growth rate.
Subjects and Methods
Inclusion criteria
Included were children with nonsystemic polyarthritis or systemic JCA, fulfilling the American Rheumatism Association classification criteria (24), aged under 14 yr, with prepubertal status [stage 1 on Tanner scores for breast and pubic hair development (25)] and growth velocity (GV) below 0.3 SD score (30th percentile) for chronological age during a minimum of 6 months preceding inclusion, who had received GC treatment with a relatively stable dose for more than 6 months before inclusion. Exclusion criteria were endocrinopathy or other metabolic or congenital disorders, renal failure, nephrotic syndrome, diabetes, heart failure, liver failure, and previous treatment with GH.
Description of patients
Forty-six prepubertal children with severe systemic or nonsystemic polyarticular JCA and growth retardation were enrolled. All patients were tested for GH deficiency (GHD) by pharmacological stimulation (clonidine). If serum GH rose to less than 20 mU/ml, a second test was performed (arginine or insulin). Nine children were thus considered GH deficient. Eight patients entered puberty within 2 yr of follow-up and were excluded from the study. Three patients withdrew and are not part of the results. Two patients were not compliant and refused to attend regular follow-up after 1 yr, but were included for the first year. One girl with GHD according to two tests developed fever with reactivation of her disease at the beginning of GH treatment and stopped therapy after 1 wk; she was included in the control group.
The mean age of the remaining 35 children at onset of arthritis was 3.7 yr; the mean duration of steroid treatment was 3.5 yr. The disease began before 5 yr of age in 24 of 35 children. The mean age at the beginning of the study was 8.9 yr (range, 4.2–12.9 yr). The mean body mass index was at the 25th percentile; 5 patients were obese due to high GC doses.
Current medication
All children were receiving GC daily. Regular drug therapy was modified as necessary by the disease state, including nonsteroidal antiinflammatory agents, slow-acting antirheumatic agents, methotrexate, or cyclosporin A and GC.
Study design
All children were measured for at least 6 months before enrollment and randomization; growth data were available at least 12 months before the study. GH was then given for 2 yr. During the study, clinical assessment was performed every 3 months in the treated groups and every 6 months in the untreated group. Three consecutive measurements of standing height were obtained with a stadiometer, and the mean was taken. In each patient joint involvement was assessed clinically by the same experienced rheumatologist, and pubertal stages were graded with Tanner scores (25) by the same experienced endocrinologist. Skeletal age was assessed every 12 months, on the average, according to the Greulich and Pyle (26) method on radiographs of the left hand. We defined successful GH treatment as an increase in GV of more than 2 SD score compared with pretreatment values.
The study was approved by the university’s ethics committee, and informed parental consent and patient assent were obtained.
Treatment regimen
Patients with GHD received human GH (hGH; Genotropin, Pharmacia, Erlangen, Germany) in a substitutional dose of 0.5 IU/kg BW·wk (5 patients). The remaining 30 patients were randomly allocated to either a study group that received treatment with 1 IU/kg BW·wk hGH (14 patients) or a control group that received no treatment (16 patients). GH was given every night by sc injections. Most children learned to give their own injections under parental supervision.
Hematological and biochemical assessments
Every 3 months blood samples were taken for measurement of hemoglobin, white cell and platelet counts, erythrocyte sedimentation rate, C-reactive protein (CRP), urea, creatinine, fasting glucose, glycosylated hemoglobin (HbA1c), cholesterol, albumin, calcium, phosphate, and alkaline phosphatase (aP). Every 6 months serum IgG, IgM, and IgA were measured, and serum protein electrophoresis was performed.
Hormonal assessment
Before hGH therapy and every 3 months thereafter, IGF-I and IGFBP-3 were measured. Thyroid function, 25-hydroxyvitamin D, and PTH were measured at least every 6 months. Plasma GH was measured using an immunoenzymetric assay (HGH EASIA, Biosource Technologies, Inc., Fleurus, Belgium), IGF-I was measured using an immunoenzymetric assay (OCTEIA IGF-I, IDS, Boldon, UK), and IGFBP-3 was measured by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA).
Assessment of bone metabolism
Every 6 months bone-specific aP (baP) and C-terminal propeptide of type I collagen (CICP) were measured. For the measurement of CICP we used an enzyme immunoassay (Metra Biosystems, Osnabrick, Germany), for aP we used a colorimetric assay in accordance with a standardized method (Roche, Indianapolis, IN), and baP was determined by measuring the remaining aP activity in the supernatant after precipitation the baP using a precipitant, a lectin from wheat germ (Roche). All enzyme activities were measured with a Hitachi 917 analyzer (Hialeah, FL).
Statistical assessment
Growth rates are presented as annualized growth velocities (centimeters per yr) calculated over a period of 6 months and as SD scores according to Prader (27). The significance of differences was calculated between treatment groups at different time points using repeated measure mixed models, accounting for the baseline value and using a first order autoaggressive covariance structure (ANOVA). Unpaired t tests and nonparametric Mann-Whitney tests were also used. A two-tailed probability of P < 0.05 was accepted as statistically significant. Correlation was assessed by Pearson’s correlation.
Results
Patients
Thirty-five patients were suitable for evaluation. Two patients
from the study group failed to complete the study because they disliked
the sc injections and stopped therapy after 1 yr. The characteristics
of the three groups (study, GHD, and control groups) at trial entry are
shown in Table 1
. There was no
significant difference among the three groups in classification of JCA,
age at onset of JCA, daily glucocorticoid dose, height, and height
velocity SD score. The patients of the study and GHD groups
were significantly older, had a longer duration of illness, and
consequently had higher corticosteroid cumulative doses than the
patients in the control group (data not shown). There were more female
patients in the control group. All but five patients were below the 3rd
percentile for height, and some of them were extremely short. All of
the patients had a height velocity of less than the 30th percentile.
Due to the significantly higher chronological age, the bone age (BA)
was higher in the treated groups compared with the control group. The
mean BA was 7.8 yr (range, 2.5–12 yr) in the study group and 9.8 yr
(range, 5–12 yr) in the GHD group, whereas in the control group the
mean BA was 6.2 yr (range, 2.5–10 yr; P < 0.05). Bone
destructive and functional signs of the left hand were evaluated by the
Steinbrocker criteria (28). All three groups were at
stages I–III, on the average.
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All patients remained on glucocorticoid treatment throughout the
study; the dose was expressed as prednisolone equivalent per kg BW/d.
The mean steroid dose decreased during the study period in the study
and control groups (Table 2). There was
no significant difference in the amount of prednisolone equivalent
among the three groups. In the study group, mean prednisolone
equivalent doses fell from 0.22 at the start of the study to 0.17 and
0.16 mg/kg BW·d after 1 and 2 yr, respectively; in the GHD group,
they remained at 0.16, 0.18, and 0.19 mg/kg BW·d at the beginning and
after 1 and 2 yr, respectively; in the control group, they fell from
0.28 mg/kg BW·d at the beginning to 0.25 and 0.23 mg/kg BW·d after
1 and 2 yr, respectively. Most of the patients received additional
medication, such as methotrexate, cyclosporin A, nonsteroidal
antiinflammatory agents, and slow-acting antirheumatic agents. These
treatment regimens did not change significantly throughout the study
period (data not shown). Laboratory variables of disease activity, such
as erythrocyte sedimentation rate, CRP, platelet count, and Hb, were
not significantly different among the three groups at the beginning and
throughout the study (Table 2).
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During the 2 yr of treatment, the median GV SD score
increased from -2.9 to +0.85 and +0.25 before and after 1 and 2 yr,
respectively, in the study group, from -3.1 to -1 and -0.45 in the
GHD group, and from -3.2 to -2.2 and -1.2 in the control group (Fig. 1). Within each group, values at
different time points were compared with each other and with the
baseline. After repeated measures analysis, the over-time difference in
GV SD score between study and control groups was
significant (P < 0.012); it was not significant
between GHD and control groups (P = 0.07). The
difference in GV SD score between study and
control groups decreased during the study period. GH treatment
increased GV significantly compared with baseline in all but three
children, although the magnitude of this effect varied markedly from
one patient to another. In the control group, GV also increased
slightly throughout the study period of 2 yr. There was no
statistically significant difference between pretrial GV in the two hGH
treatment groups, but the response was greater in patients receiving 1
IU/kg BW·wk compared with those receiving 0.5 IU/kg BW·wk.
Improvement in GV was observed regardless of the subgroup of JCA, but
the number of nonsystemic polyarticular JCA patients was small. The
observed increase in growth rates in the patients receiving hGH
treatment could not be accounted for simply by age. In comparison with
the control group the treated patients grew better, although they were
older, but none of them had entered puberty. Figure 2 shows the median height
SD score over the 2-yr study period. The height
increment over the 2-yr period was 14.9 cm in the study group, 8.9 cm
in the GHD group, and 8.0 cm in the control group. After repeated
measures ANOVA, the over-time difference in height
SD score between study and control groups was
significant (P < 0.012); it was not quite significant
between GHD and control groups (P < 0.06). Taking all
patients together, there was an inverse correlation between GV
SD score (0–1 yr) and prednisolone equivalent
(r = -0.4; P < 0.01), height increment and
prednisolone equivalent (r = -0.52; P < 0.001),
and GV SD score and CRP (r = -0.6;
P < 0.01). There was no correlation between cumulative
GC dose and pretrial height SD score or GV
SD score.
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, upper panel). IGFBP-3
levels increased significantly in the two treated groups (Fig. 3, lower panel). In the control group IGF-I and IGFBP-3
remained low. Mean GHBP values were also low, but increased in all of
our patients from the 10th percentile to the 45th percentile (data not
shown).
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Bone formation and hormonal assessment
Regardless of the disease activity the majority of the children
studied had normal values for blood ionized calcium and phosphate,
thyroid function, PTH, and 25-hydroxyvitamin D. Throughout the study
period these parameters remained within normal limits. aP and baP as
well as CICP were within the lower normal range at the start of the
study (Table 3). After 2 yr of study, aP,
baP, and CICP increased significantly within the study group by 97%,
181%, and 62%, respectively. In the GHD group there was also a
marked, but not significant, increase from baseline to 2 yr of
treatment in aP, baP, and CICP of 52%, 71%, and 63%, respectively.
Within the control group over the 2 yr there were also slight increases
in aP, baP, and CICP of 30%, 51%, and 36%, respectively (Table 3).
There was a significant correlation (r = 0.45; t <
0.001) between CICP after 6 months of GH therapy and the amount of
height gain after 2 yr. Joint functional status according to
Steinbrocker did not change during the study and remained at stages
II–III.
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The joints were examined by the same experienced rheumatologist. There was no significant change in joint involvement during the study period in any of the three groups. There was no significant change in blood pressure over the study period (data not shown). Some parents reported an improvement in their child’s well-being and activity during hGH therapy.
In the whole group of patients there was no significant difference
between laboratory values at the start of the study and after 2 yr
(Table 3
). Fasting glucose, urea, creatinine, cholesterol, albumin, Ig,
and serum protein electrophoresis remained within normal ranges.
Glucose homeostasis was evaluated by HbA1c
measurements and fasting glucose levels. Throughout the study none of
the children involved had fasting glucose levels over 110 mg/dl.
HbA1c levels did not change (Table 2). TSH levels
were unchanged throughout the study.
Assessment of other effects of hGH treatment
None of the patients complained of headaches. Every 3 months patients were investigated by an oculist. One patient had papilledema, but this had been present before treatment and did not change during therapy. Fundoscopy and visual acuity were stable. One patient received synovectomy of the hip joint due to severe synovitis. One patient with marked contractures of hips and knees experienced a worsening of lumbar lordosis. No slipped capital femoral epiphysis was observed. In the control group one patient died 2.5 yr after the start of the study of severe systemic JCA with polyserositis.
Discussion
Growth retardation and short stature are well recognized problems in children suffering from JCA, in particular in systemic or nonsystemic polyarticular-onset forms of the disease (2, 4). Long duration of disease activity, therapeutic intervention, especially the use of glucocorticoids, immobilization, and malnutrition have been implicated as contributing factors for the abnormal growth in JCA (29, 30, 31, 32). Bernstein (33) compared patients with JCA and SLE receiving equivalent steroid doses and found those with JCA to be much more growth-retarded than those with systemic lupus erythematosus, suggesting an additional problem inherent in the disease. One reason might be the different cytokine patterns of the diseases (34, 35, 36). Ansell (2) observed growth failure in times of active disease and a return to normal growth with remission.
With the recognition of GH secretion and IGF-I production as a predominant stimulus for growth, studies have been initiated to investigate possible abnormalities in chronic diseases. In GH stimulation tests with pharmacological stimuli, most of the children with JCA showed no abnormalities. Nevertheless, as in our study a disturbance of GH secretion with pharmacological stimuli has been found in some children (37, 38, 39). In our study the serum GH concentration after clonidine and arginine or insulin administration did not increase over 20 mU/ml in 9 of 46 children. GH is secreted in a pulsatile fashion, mainly during sleep (40); abnormalities in this physiological pattern of secretion, particularly in the amplitude and number of pulses, have been reported in children with JCA (37). Almost half of the children in the study by Touati et al. (23) showed abnormalities in the spontaneous secretion of GH.
There are several studies showing increased rates of growth resulting from exogenous GH treatment in children with JCA (10, 19, 21, 22, 23). The majority of patients showed an acceleration of growth rate from the beginning of therapy. Not every patient responded to hGH in the same way. We observed improvement in GV in our treated and untreated groups. The improvement in the study group was more marked than that in the GHD and control groups. Compared with baseline, the GV SD score in the study group was significantly higher after 1 and 2 yr. The GV SD score in the GHD group increased throughout the study period; this increase was not statistically significant, probably due to the small number of patients or the lower hGH dose (0.5 IU/kg BW·wk vs. 1.0 IU). Interestingly, a significant improvement in GV SD score also occurred in the control group after 2 yr compared with baseline. This underlines the importance of having a control group in such studies. In times of high disease activity and high doses of GC used to control disease, growth rate has been shown to be impaired (41). We found a significant correlation between GV SD score, and prednisolone equivalent and CRP (r = -0.4 and r = -0.6; P < 0.01). Therapy with hGH can only partly reverse this negative effect. Whenever disease activity decreased, catch-up growth occurred in the two treated groups, but also to a lesser extent in the control group. Overall, height retardation stabilized during GH treatment and worsened in the control group. The stabilization of the relative position on the growth curve of these children indicates a beneficial response to hGH (20).
Children in the study group with a higher dose of 1 IU/kg BW·wk responded better than children in the GHD group. This may indicate a peripheral defect, with abnormalities in the GH-IGF-I axis (42, 43, 44). Regardless of stimulated GH levels, supraphysiological doses of GH may be needed to overcome the relative GH insensitivity and increase IGF-I, concordant with experiences in uremic children and in children after renal transplantation treated with hGH (45, 46).There was no correlation between stimulated peak GH levels and response to hGH therapy. Of course, multiple factors influence GV in JCA, and only one of these is GH.
We and others have shown that children with JCA have low levels of IGF-I and IGFBP-3, as an indicator of GH resistance (13, 14, 15). Before hGH treatment the levels of IGF-I and IGFBP-3 were at the lower end of the normal range in all of our patients. The GV improvement in the treated patients was associated with a significant increase in IGF-I and IGFBP-3 serum levels. In the control group IGF-I and IGFBP-3 levels remained at the lower normal level. Aitman et al. (14) found a significant correlation between growth failure and serum IGF-I. In the studies by Davis and Touati (22, 23), IGF-I levels increased during hGH therapy.
Low IGF-I is not only associated with impaired growth but also plays an important role in the pathophysiology of osteoporosis. Johannson at al (47) treated young men with IGF-I and found within 1 wk a significant increase in markers of bone formation. Parameters of bone formation, such as baP and osteocalcin, noncollagenous proteins that are released into circulation during bone synthesis, and CICP, a by-product of the enzymatic conversion of procollagen to collagen, are reduced in JCA due to immobilization, disease activity, and medication (48, 49, 50). They increased after treatment with hGH (20). CICP especially may represent an early index of metabolic effects and a predictive biochemical marker of the increased GV during GH treatment (51). We found a significant correlation between height gain after 2 yr and CICP after 6 months of the study. In the treated groups aP, baP, and CICP increased and were stable at a higher level; in the control group these markers increased to a lesser extent. According to a study by Reed et al. (52), decreased mineralization during disease activity could be followed by a reparative process coincident with the resolution of inflammation. Kontamieni (53) showed that children with JCA had a significantly reduced bone mineral density, with a 10–20% decrease in the lumbar spine, which persists into adulthood (54). Osteoporosis and consecutive fractures are likewise well documented (17). The major factors associated with osteopenia are the same as those causing growth deficiency, namely, severe disease and GC administration.
There were no clinical or laboratory side-effects from hGH therapy. Fasting glucose, HbA1c, and TSH remained normal throughout the study. Treatment with hGH may induce resistance to insulin, especially in combination with exogenous GC administration. We and others (20, 23) have observed a small rise in fasting glucose but not overt diabetes mellitus. HbA1c remained stable in all of our patients throughout the study period. Disease activity did not change during the study. We did not observe any osseous complications. Many parents reported that their children were more active and their exercise capacity increased. Such an effect of GH on well-being and quality of life has been described in GHD, small for gestational age, Turner syndrome, and Prader-Willi syndrome (55).
We conclude that in JCA, as in other chronic inflammatory diseases in childhood associated with growth impairment, treatment with hGH is effective in promoting linear growth. The best chance of successful outcome is when disease activity is mild, and supraphysiological doses of hGH are used. Whether in times of high disease activity and higher doses of GC, growth impairment can be overcome by increasing doses of hGH without toxicity is unknown. Long-term controlled studies are essential to evaluate the effects of hGH on bone formation and final height. Of equal importance is the evaluation of a potential risk of high dose hGH therapy. Further studies and new insights into the pathophysiology will be necessary to select patients who will benefit from hGH therapy.
Acknowledgments
We thank Drs. Elfriede Said and Heinz Steinkamp (Pharmacia, Erlangen, Germany) for supporting this study.
Footnotes
Abbreviations: aP, Alkaline phosphatase; BA, bone age; baP, bone-specific alkaline phosphatase; CICP, C-terminal propeptide of type I collagen; CRP, C-reactive protein; GC, glucocorticoids; GHD, GH deficiency; GV, growth velocity; HbA1c, glycosylated hemoglobin; hGH, human GH; IGFBP-3, IGF-binding protein-3; JCA, juvenile chronic arthritis.
Received March 15, 2001.
Accepted August 29, 2001.
References
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