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Volume 3 Number 2 |
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CLINICAL
REVIEW ARTICLE JIA-associated growth failure and
exogenous growth hormone therapy Timothy
G. Beukelman1, Randy Q. Cron1,2 Division
of Rheumatology, 1Children’s Key
Words: juvenile idiopathic arthritis
(JIA), growth hormone, therapy, growth failure, corticosteroids, insulin-like
growth factor (IGF) Contact:
Timothy
Beukelman, MD Children’s
Division
of Rheumatology 3405
Civic Tel: (215) 590-0685 FAX: (215) 590-4750 E-mail: beukelman@email.chop.edu Abbreviations: juvenile idiopathic arthritis, JIA; growth
hormone, GH; insulin-like growth
factor, IGF; height standard deviation score, HSDS; growth velocity, GV;
growth velocity standard deviation score, GVSDS; anti-tumor necrosis factor
alpha, anti-TNFa; interleukin-6, IL-6 Abstract Children with juvenile idiopathic arthritis (JIA)
are often growth delayed, in particular, those with long-standing systemic
onset disease. Total body inflammation and corticosteroid therapy are
strongly implicated as causes of growth failure in JIA. Treatment of
JIA-associated growth failure with growth hormone (GH) therapy has been
successful to varying degrees. The financial cost and potential for disease
exacerbation should be considered when utilizing GH therapy in JIA. The
benefits afforded by novel biologic disease modifying agents may obviate the
perceived need for GH therapy. Introduction Growth failure in juvenile
idiopathic/rheumatoid/chronic arthritis (JIA) has been well described (1). The
majority of children with JIA and growth failure are of the systemic onset
subtype, with smaller numbers of polyarticular and even less oligoarticular subtypes
[1, 2]. Growth
failure is almost certainly multi-factorial and several potential mechanisms have
been proposed. Inflammation and corticosteroid therapy are the
most commonly implicated factors in JIA-associated growth failure. Glucocorticoids alone are well-known
inhibitors of growth [3].
Difficulty exists in differentiating the contributions of inflammation
from the increased corticosteroids that often accompany it. However, growth failure has been shown to
occur in children with JIA independent of corticosteroid treatment [4] and even in the total absence of steroid therapy [5]. The role
of exogenous growth hormone (GH) therapy in growth failure in children with
JIA is controversial and herein, reviewed. Growth hormone and the pituitary axis
in JIA Both inflammatory cytokines and corticosteroids
influence GH production and its effects.
Abnormalities of the GH-pituitary axis have been described in children
with JIA. Depending on the testing
method employed, 20-50% of JIA patients with poor growth and chronic steroid
therapy are GH deficient [6-8]. Studies
have shown that corticosteroids likely inhibit the GH axis on several levels,
including suppression of GH releasing hormone-stimulated GH release,
decreased GH pulsatility, suppression of transcription of GH receptor, and
decreased GH and insulin-like growth factor-1 (IGF-1) receptor binding [9]. The primary mediators of GH effects are IGF
proteins, and children with JIA with growth failure have impaired IGF
production [6, 10-12]. Both
height standard deviation scores (HSDS) and growth velocity (GV) correlate
with IGF levels in these patients [13]. In
addition, IGF levels have been shown to correlate inversely with erythrocyte
sedimentation rate (ESR) [14], but not steroid dose [13, 14]. During
treatment with exogenous GH, IGF levels are negatively correlated with
C-reactive protein (CRP) levels [10]. IGF
levels have also been shown to correlate inversely with interleukin-6 (IL-6)
levels [15], which are known to be elevated in systemic onset
JIA [16]. Thus, IGF
levels may be a surrogate marker for growth in JIA. Growth failure in JIA Growth failure occurs relatively frequently in JIA.
The natural history of growth failure in 24 children with systemic onset JIA
treated with steroids for at least two years showed that the mean HSDS
decreased significantly from -0.03 at time of diagnosis to –2.4 over four
years and the mean final adult HSDS was –2.0, with 41% of subjects’ height
more than 2 SD below the mean.
Eighty-seven percent of subjects finished below target height based on
mid-parental height, though if mid-parental heights were used as a target
height, the HSDS loss was smaller at –1.7.
Actual male final mean height was
1.64 m (range 1.45 to 1.80) [or 5’5” (4’9” - 5’11”)], and actual
female final mean height was 1.50 m (range 1.34 to 1.65) [or 4’11” (4’5”
- 5’5”)]. These final heights demonstrated significant
growth failure in many of these children. [17] This study demonstrated a strong positive
correlation between mean HSDS loss during prednisone therapy and duration of
prednisone therapy [17]. This correlation has also been shown for
cumulative steroid dose [18].
Conversely, following discontinuation of prednisone an average
increase in HSDS of 0.45 was observed.
However, this catch-up growth was dichotomous; 70% experienced
catch-up growth and increased their HSDS by a mean of +1.0 to a final of
-1.5, while the other 30% had further mean HSDS loss of –0.8 for a final of
-3.6. The factors contributing to the
presence of catch-up growth are unclear, but appear to partially depend on
the genetic potential for growth [17]. Observational growth hormone studies
in JIA Observational
studies of exogenous GH therapy for JIA-associated growth failure are shown
on the Table 1. Table 1– Studies analyzing
growth hormone therapy for JIA Ref. Author Year
Study type (n) Summary 19 Butenandt 1979 Observational 20 in GV by 4.3 cm/yr in 75%. 20 Davies 1994 Observational 20 in GV by 4.1 cm/yr. 21 Touati 1998 Observational 14 in GV by 3.5 cm/yr. 6 Al-Mutair 2000 Observational 10 in GV by 3.0 cm/yr in 6 of 10 22 Simon 2003 Observational 13 in GV by 3.9 cm/yr. 18 Bechtold 2003 Controlled 18 Increase
in GV compared to controls. 8 Saha 2004 Controlled 25 Increase
in GV compared to controls. GV, growth velocity. In 1979, Butenandt described 20 children with JIA
with growth failure given GH therapy.
Mean GV increased from 1.9 cm/year to 6.2 cm/year in the 75% of
subjects who responded [19]. More
recently, Davies et al. reported on 20 children with polyarthritis (10
systemic onset, 8 polyarticular onset, 2 pauciarticular onset) and a growth
velocity standard deviation score (GVSDS) < -1.0. Subjects were randomized to receive two
different doses of GH for one year and were then followed for six additional
months. The higher dose GH increased
GV by a mean of 4.1 cm/yr (mean GVSDS increased from –2.9 to +0.5). There was no statistical correlation
between prednisone dose and response to GH, although a decrease in GV was
noted in individuals when steroid doses were increased. Additionally, there was a highly
significant negative correlation between mean serum CRP levels and GV. Lastly, children with polyarticular and
pauciarticular onset experienced greater improvement in GV than those with systemic onset [20]. Touati et al. reported on GH therapy for 14
children with systemic or polyarticular onset JIA who were on chronic oral
steroids and exhibited growth failure (GV was at least 1 SD below the mean
and height was more than 2 SD below the mean). At one year of therapy, the mean GV had
increased from 1.9 cm/year to 5.4 cm/year.
As expected, there was a highly significant inverse correlation
between GV during treatment and steroid dose [21].
Similarly, Al-Mutair et al. reported 10 patients with growth failure
on prednisone therapy for polyarticular or systemic onset JIA. Mean GV in the first year of treatment increased
significantly from 2.45 cm/year to 4.79 cm/year and, in a subset of 6
children who continued on GH therapy for a second year, it continued to
improve to 5.43 cm/year [6]. A recent observational study by Simon et al.
described 13 children with polyarticular or systemic onset JIA and growth
failure who received GH for 3 years.
Patients continued to have active disease throughout the study as evidenced
by persistently elevated ESR and prednisone doses >0.2 mg/kg/day. Nevertheless, median GV increased
significantly during the first year of GH therapy. However, the median HSDS did not
change. Seven of the 13 children (54%)
experienced catch-up growth and increased their mean HSDS by +0.6, but 4 of
13 (all of whom had high ESR or high steroid dose) had no catch-up growth and
had a decreased mean HSDS of –0.4 [22]. These results suggest that improved disease
control, with resultant lower steroid doses, is perhaps the most important approach
to improving growth in children with JIA. In
summary, multiple observational studies have shown a short-term statistically
significant increase in GV with GH therapy.
Both active disease and steroid therapy likely decrease the
effectiveness of GH, and upon discontinuation of GH there is a significant
fall in GV toward pretreatment levels [20], perhaps as low as pre-treatment levels [21]. Taken together, all these observational GH study
results appear encouraging for improving GV for children with JIA, but there
is no convincing data on final adult height.
All the same, the stage is set for randomized controlled trials of GH
for the treatment of growth failure in children with JIA. Controlled trials of growth hormone
therapy in JIA In addition to observational studies, two
controlled trials of GH for growth failure in JIA have been published. Saha et al. studied 25 children with active
JIA, height below mean, and GV more than 1.5 SD below mean [8]. In this
crossover study, patients served as their own controls. Each received either GH or placebo for 6
months followed by 6 months of the other therapy. The distribution of diagnoses was, in
contrast to most other studies: 12% systemic, 40% pauciarticular, and 48%
polyarticular onset JIA. Only 56% were
taking daily steroids. In this cohort, GH therapy resulted in a >50%
increase in GV, versus placebo, in 75% of the patients. In those treated with GH, mean HSDS also
increased from -2.08 to -1.79, compared to an increase from -2.18 to -2.02
for placebo. Additionally, children
with GH deficiency as measured by L-dopa stimulation had a similar pattern of
response to GH therapy as those without deficiency. Of note, this study excluded patients with
“labile” arthritis requiring steroid treatment several times daily or those
with recent activation of arthritis likely to require such therapy during the
trial period. Thus, the benefit of GH therapy for patients with notably
active JIA was not adequately addressed. In 2001, Bechtold et al. published a 2-year
controlled study of children with established JIA and a stable corticosteroid
dose for >6 months whose GV was below the 30th percentile for
chronological age [7].
Thirty-three of the 35 children had systemic onset JIA. The patients were divided into 3
groups. Subjects found to be GH
deficient were given physiologic GH replacement for two years, and those
without GH deficiency were randomized to receive either supra-physiologic
exogenous GH for 2 years or no GH therapy.
The GH study group showed improved GV compared to
controls (P<0.012). Specifically,
the study group mean GVSDS was -2.9 at onset, improved to +0.85 at one year
of therapy, and was +0.25 at two years.
In comparison, the control group mean GVSDS was -3.2, -2.2, -1.2
during the same time intervals. The GH
deficient group receiving GH replacement improved their GV, but not
significantly (P=0.07) compared to the control group. In terms of clinical significance, the GH
group grew a mean of 14.9 cm versus 8.0 cm for the control group for a mean
actual height increase of 6.9 cm (2.7 inches). Assessing all patients together, both
corticosteroid dose and CRP showed a significant inverse correlation with GV,
as predicted from the observational studies.
These same patients, with a few
additions, were published again by Bechtold and colleagues in 2003 [18]. At four
years of GH therapy, the GH treatment group had an increased mean HSDS from
-3.3 to -2.3, whereas the control group mean HSDS decreased from -2.3 to
-3.0, for a net increase of 1.7 SD for the treatment group. The controls did increase their GVSDS
through the four years from -2.6 to -0.8.
Multiple regression analysis revealed that height gain was most
influenced in an inverse fashion by mean ESR, mean CRP, and mean prednisone
dose. Specifically, GH treatment
resulted in a higher GV for a given prednisone dose, but high doses of
prednisone tended to negate the effects of GH and resulted in smaller height
gains. A significant inverse
correlation was found between GV and joint activity score. This again
suggests that effective disease control is requisite for optimal growth. Although the study by Bechtold et al. is perhaps
the most useful study yet reported regarding exogenous GH therapy for growth
failure in juvenile arthritis, it has limitations. The obvious major limitation of this study,
freely admitted by the authors, is the lack of follow-up to adulthood, i.e.,
final height. Delayed puberty in these
patients may require follow-up into their early twenties, particularly for
males, to assure final height. Also
presented but less explicitly mentioned was the fact that although the
control and study groups did not have statistically different mean steroid
doses at the onset of the study, by the fourth year the control group was on
a higher steroid dose (0.17 mg/kg/d of prednisolone equivalent versus 0.10
mg/kg/d, P<0.05). Similarly, the
control group contained more individuals receiving > 0.2 mg/kg/d of
prednisolone equivalent (7 of 20 versus 3 of 18). This makes it more difficult to directly
compare the benefit of GH therapy for GV in JIA since corticosteroids have
clearly been shown to inhibit growth. Even so, the studies by Saha and by
Bechtold and their colleagues suggest that GH therapy may improve GV in
children with active JIA. Indications and risks of growth
hormone therapy for JIA The indications for GH therapy in JIA-associated
growth failure are still not clear and the current use of GH for growth
failure outside of GH deficiency remains very controversial [23]. GH
therapy is not currently FDA approved for use in JIA in the The potential for GH-induced activation of the
immune system is an interesting consideration. Most studies state that disease activity
and/or joint scores were unaffected by GH therapy [7, 8, 18, 20, 21]. However,
two patients failed to complete one study because of severe disease flare on
GH therapy [20]. One study
excluded patients with “labile” arthritis who may have been more likely to
flare [8]. In
another study, one patient developed fever and flare of disease at the onset
of GH therapy [7].
Additionally, there is a case report of systemic lupus erythematosus
flare thought to be related to exogenous GH [25]. Although
these cases may implicate GH in disease flares, they are certainly not proof
of cause. In addition to anecdotal reports, there are several
observations that raise concern that GH may possibly contribute to flares of
autoimmune disease. IGF-1 has been
shown to be increased by exogenous GH therapy [7, 10, 21, 22], and both IGF-1 and GH have numerous effects on
mouse thymocytes, including stimulating proliferation and augmenting
trafficking [26]. Similar
effects on human thymocytes would not be surprising, as GH and its receptor
are known to be expressed by human thymic cells [27]. GH may
also have positive effects on the functional activity of circulating
phagocytic cells as suggested by the correction of phagocyte dysfunction in
GH deficient children who received GH therapy [28]. Finally,
transgenic mice expressing bovine GH develop an arthritic disorder with
disability and significant thickening of synovial tissue. The arthritis is presumed autoimmune in
nature based on the concomitant presence of multiple autoantibodies [29]. This animal model perhaps raises suitable
concern for the use of GH in children with JIA. The available literature suggests that in addition
to medical considerations, families and physicians often take into account
age and maturity of the patient, societal and perceptual factors, and financial
considerations when making decisions about GH therapy (30, 31). With
regards to financial considerations, the current cost of a one year supply of
GH for a 30 kg patient is in excess of $15,000 (23). This cost is on par with the current annual cost
for TNFa inhibitors used to
treat JIA (32). Given the important role of disease activity in
growth failure, limited resources would likely be better spent on therapies
aimed at controlling inflammation. Disease control and growth Since growth has been shown to improve with better
disease control and/or lower doses of corticosteroids, the introduction of
more effective biologic agents may greatly decrease the incidence of growth
failure and obviate the need for GH therapy.
In one of the observational GH therapy studies, 2 patients went into
remission during the pretreatment observation period and had a subsequent
growth spurt, thus disqualifying them from the study [20]. Moreover, a retrospective study reviewed the growth
of 71 patients with polyarthritis; only 2 had systemic onset JIA. Their growth was reported for 2 years
before and 2 years after instituting anti-tumor necrosis factor alpha
(anti-TNFa) therapy. In 53 children with growth impairment prior
to therapy, the mean change in HSDS per year was +0.45 SD. Additionally, the mean total dose of
corticosteroids for all patients decreased from 3.2 gm in the preceding 2
years to 1.6 gm in the 2 years following treatment (50% reduction) [33]. Thus, in
the absence of exogenous GH, children with JIA improved their growth when
their disease activity was controlled. In addition to anti-TNFa therapy, other novel biologic strategies are
becoming available. One example is
interleukin-6 (IL-6), which has been strongly implicated in the pathogenesis
of systemic onset JIA [16], and anti-IL-6 receptor antibodies have shown
promise in the treatment of this condition [34, 35].
Similarly, a mouse model of IL-6 over-expression has been shown to
result in stunted growth which can be partially overcome with the
administration of anti-IL-6 antibodies [15]. Lastly,
in a human study, four children with systemic onset JIA and a starting height
ranging from -0.4 to -7.1 SD experienced a height increase of between +0.2 and +1.6 SD during a 2 to 3.5 year
course of anti-IL-6 receptor therapy [36]. With
newer, more effective therapies available for difficult to treat JIA, growth
failure may become less of a co-morbidity for these children. Conclusions There is no doubt that growth failure occurs in
JIA, especially in children with long-standing systemic onset disease. Growth failure is likely multi-factorial,
although cytokine aberrations and sustained corticosteroid therapy seem to
play a central role. Exogenous GH
therapy has been shown to promote growth in these children, even in the
absence of a measurable GH deficiency.
The clinical significance of this growth varies on an individual
basis, and the effect of GH on adult height remains unclear. Although few concerning side effects of GH
therapy have been reported in clinical trials, there are theoretical risks of
disease exacerbation by many mechanisms.
Irrespective of GH therapy, disease remission has been shown to
promote growth. Hopefully, the advent
and use of directed biologic agents will bring about more effective disease
control and an end to growth failure associated with JIA. Acknowledgement The
authors thank Dr. David D. Sherry and References 1. Bernstein BH,
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