Impact Of Chronic Rheumatic Disease On Growth And Development

The two main disturbances of growth and pubertal development seen in young people with chronic rheumatic disease are growth failure and

Table 1 Average Age of Pubertal Development

Females Males

Females Males

Table 1 Average Age of Pubertal Development

Average

Bone

Average

Bone

Pubertal event

age

Stage

age

age

Stage

age

Puberty onset

Breasts

10.5

B2

11

Genitalia/

11.5

G2 O4

12

testes

Pubic hair

11

P2

12-12.5

P2

Menarche/

12-13

B3-4

14

G3-4

spermarche

Start of height

11

B2

11

12.5

G2-3

13

spurt

O6-8

Peak of height

12

B2-3

14

13.5

G3-4

14

spurt

Puberty end

14-15

B5 P5

15

16-17

G5 O20-25 P5

17

Abbreviations: B, breasts; G, penis and scrotum; O, testes volume as per orchidometer; P, pubic hair.

Abbreviations: B, breasts; G, penis and scrotum; O, testes volume as per orchidometer; P, pubic hair.

pubertal delay. Young people with such conditions may experience either condition or both. Together they can result in short stature, reduced bone density (see Chapter 12), low self-esteem, poor body image, and delayed development of the psychosocial tasks of adolescence (see Chapter 1).

Outcome studies in juvenile idiopathic arthritis (JIA) from as early as the 1950s and up to the present day describe significant generalized and localized growth disturbances, short stature, and shortened bones respectively. Conclusions from these studies have changed little from the earlier descriptions by Ansell and Bywaters in 1956 (7). They found from a survey of 119 children less than 14 years of age with Still's disease (now known as JIA systemic onset) that disease activity retarded growth resulting in infantile proportions and that this was exacerbated by systemic steroid treatment. In addition, they saw catch-up growth during disease remission, especially in the younger children, but not in those with longstanding and severe disease activity.

Subsequent studies have found that growth failure is most severe in the systemic onset and polyarticular subtypes of JIA and particularly those with a more severe course and/or treated with systemic steroids. The individual contribution from each of these two factors is difficult to establish. Zak et al. found the mean final height of 65 adults with all subtypes of JIA to be —0.25 standard deviation score (SDS), not significantly different from the general population (8). However, their heights were not normally distributed, and 10.7% had a final height more than two SD below the general population mean. Just over a quarter also had significantly reduced arm span, a

Tanner Stages

Figure 6 Tanner stages 1-5 (A) for female breast development. Stage 1: Preadolescent: elevation of papilla only. Stage 2: Breast bud stage: elevation of breast and papilla as small mound. Enlargement of areola diameter. Stage 3: Further enlargement and elevation of breast and areola, with no separation of their contours. Stage 4: Projection of areola and papilla to form a secondary mound above the level of the breast. Stage 5: Mature stage: projection of papilla only due to recession of the areola and general contour of the breast. Tanner stages 1-5 (B) for female pubic hair development. Stage 1: Preadolescent: The vellus over the pubes is not further developed than that over the abdominal wall, i.e., no pubic hair. Stage 2: Sparse growth of long, slightly pigmented downy hair, straight or slightly curled, chiefly along labia. Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the junction of the pubes. Stage 4: Hair now adult type, but the area covered is still considerably smaller than in the adult. No spread to medial surface of thighs. Stage 5: Adult in quantity and type with distribution of the horizontal (or classical "feminine") pattern. Spread to the medial surface of the thighs but not up the linea alba or elsewhere above the base of the inverse triangle (spread up linea alba occurs late and rated stage 6).

Pubic Hair Male

Figure 7 Tanner stages 1-5 for male pubic hair and genitalia development. Pubic hair stages (A) as per females (see page 41). Tanner stages 1-5 (B) for male genitalia development. Stage 1: Preadolescent: testes, penis and scrotum are of about the same size and proportion as in early childhood. Stage 2: Enlargement of scrotum and testes. Skin of scrotum reddens and changes in texture. Little or no enlargement of the penis at this stage. Stage 3: Enlargement of penis, which occurs at first mainly in length. Further growth of testes and scrotum. Stage 4: Increased size of penis with growth in breadth and development of glans. Testes and scrotum larger; scrotal skin darkened. Stage 5: Genitalia adult in size and shape.

Figure 7 Tanner stages 1-5 for male pubic hair and genitalia development. Pubic hair stages (A) as per females (see page 41). Tanner stages 1-5 (B) for male genitalia development. Stage 1: Preadolescent: testes, penis and scrotum are of about the same size and proportion as in early childhood. Stage 2: Enlargement of scrotum and testes. Skin of scrotum reddens and changes in texture. Little or no enlargement of the penis at this stage. Stage 3: Enlargement of penis, which occurs at first mainly in length. Further growth of testes and scrotum. Stage 4: Increased size of penis with growth in breadth and development of glans. Testes and scrotum larger; scrotal skin darkened. Stage 5: Genitalia adult in size and shape.

consequence of both generalized and localized growth disturbance. Twenty-five to 30% of the variation in these growth disturbances was related to JIA subtype (systemic onset and polyarticular versus oligoarticular), systemic steroid treatment, and Steinbrocker functional class (II-IV vs. I).

More recently, a larger study of 246 adults with JIA found males and females to be on average 4.2 and 3.8 cm shorter respectively than the male

Figure 8 Prader orchidometer: Darker beads 1-3 mL indicate prepubertal testes volume; lighter beads 4-25 mL indicate pubertal development.

and female general populations (9). Reduced final height was significantly associated with duration of systemic steroid treatment, again implicating both systemic steroid treatment and disease severity.

A smaller study of 24 patients with JIA systemic onset receiving oral steroids for at least two years, retrospectively, described growth from diagnosis, through childhood disease activity to final height (10). At diagnosis mean height SDS for age was —0.03 and not significantly different from height expected for genetic potential. After 4 years of disease activity they experienced a significant loss of height with a mean height —2.7 SDS. The reduction in height velocity correlated with duration of systemic steroid. Following discontinuation of oral steroids 70% had a partial catch up in height (mean of 1 SDS) with mean final height —1.5 SDS, while 30% had persistent poor height velocity and mean final height of —3.6 SDS. The mean final height was strongly correlated with height SDS at discontinuation of oral steroids. In addition, greater catch-up growth was seen in those growing above their genetic potential at diagnosis. Overall 41% had final heights more than two SD below the general population mean, and 87% failed to attain heights within their genetic potential. This study highlighted two critical periods impacting final height, which become important when considering intervention and prevention: the active disease phase and the period following systemic steroid discontinuation.

The impact of disease activity on growth in the absence of steroid use is illustrated by Chedeville et al. (11) who showed improved height and height velocity in 21 prepubertal children with JIA who responded to Methotrexate compared to 6 prepubertal children with JIA who did not

1 A

15 1

9

ïy—^m

20 1

s

L

Îλ

y

Ç

respond to Methotrexate by one year. The improved growth was still significant after three years.

There is no published research describing growth during puberty in young people with JIA, and little describing their pubertal course. In a cohort of 13 young people with JIA (systemic onset or polyarticular requiring oral steroids) and receiving GH, 9 had entered puberty at a mean age of 12.8 years (9.6-15.4) and 15.5 (12.5-16.3) in females and males respectively (12). Rusconi et al. (13) found that menarche occurred later in 83 females with JIA compared to their mothers and healthy Italian controls, and more so in those on oral steroids or with systemic onset. Other studies have found no difference in age of menarche compared to the general population (14,15). However, clinical experience indicates that pubertal delay is common in young people with JIA systemic onset. Glucocorticoids, particularly in high doses may cause menstrual irregularities, including primary or secondary amenorrhea.

Few final height data are available from other chronic rheumatic disease groups such as the connective tissue disorders, presumably due to their lower prevalence and greater heterogeneity. Short stature in addition to asymmetric growth abnormalities have been reported in the connective tissue disorders of SLE, JDMS, and scleroderma (16). It has been shown, however, that for the same systemic steroid doses, those with JIA experience greater reductions in height than those with SLE, highlighting the disease specific contributions to growth failure (17).

The main contributing factors to growth failure are the following:

■ Chronic active systemic inflammation

■ Chronic localized inflammation (hyperemia, local growth and inflammatory factors) damaging the growth plate and accelerating epiphyseal maturation

■ Glucocorticoid treatment

Osteoporosis with vertebral collapse

■ Undernutrition (anorexia, increased caloric requirements—inflammation/infection)

■ Adverse impact of chronic illness on emotional state

■ Pubertal delay

In addition, there are issues associated with adolescent development that can impact on the course of the illness and its management, which in turn may further affect physical growth and development (18). These include:

■ Increased caloric need for the pubertal growth spurt

■ Changing hepatic and renal metabolism, necessitating medication dose adjustment n Reduced adherence to management, which may be a consequence of delayed cognitive development, competing priorities, and exploration of health risk behaviors

Figure 9 depicts the GH-IGF-1 axis regulating growth along with some of the factors leading to growth failure. The most important determinant appears to be the net circulating level of IGF-1 activity (19).

Growth hormone JJ

Growth hormone JJ

Figure 9 Mechanisms of growth failure in chronic rheumatic disease involving the GH-IGF-1 axis. Abbreviations: GHRH, growth hormone releasing hormone; IGF-1, insulin-like growth factor-1; IGFBP-3, insulin-like growth factor binding protein-3; IL-1, interleukin-1; IL-6, interleukin-6; TNF, tumor necrosis factor. Source: Adapted from Ref. 19.

Growth

Figure 9 Mechanisms of growth failure in chronic rheumatic disease involving the GH-IGF-1 axis. Abbreviations: GHRH, growth hormone releasing hormone; IGF-1, insulin-like growth factor-1; IGFBP-3, insulin-like growth factor binding protein-3; IL-1, interleukin-1; IL-6, interleukin-6; TNF, tumor necrosis factor. Source: Adapted from Ref. 19.

Glucocorticoids have a normal physiologic function in mediating catabolic processes such as proteolysis. As a consequence, in supra-physiologic amounts, such as treatment with oral steroids, growth is inhibited and height velocity slows. The mechanism for this is thought to be a combination of suppression of GH secretion, stimulation of IGF-1 inhibitors, and direct effects on the growth plate (20-22). It has been established that this occurs in doses equivalent to at least 0.25 mg per kg per day of prednisolone (23,24). Following oral or intravenous administration of prednisolone, IGF-1 activity levels fall over the first 4-6 hours respectively, with recovery by 24 hours (19). The use of alternate day oral steroids allows a period of normal IGF-1 activity, and therefore the potential for normal height velocity and growth to be maintained (19). However, disease control is not often able to be maintained with alternate day regimes and potentially may lead to protracted steroid therapy.

There have been several small studies in children with JIA assessing GH secretion as well as IGF-1 levels, with variable results. Touati et al. (25) treated 14 children with severe systemic onset or polyarticular JIA and growth failure receiving oral steroids with GH for one year. Baseline measurements revealed spontaneous nocturnal GH levels more than two SD below the mean in half the children, normal stimulated GH levels in all but one, low-normal IGF-1 levels in 12 and normal IGFBP-3 levels in all children. With GH treatment (0.46mg/kg/wk) IGF-1 and IGFBP-3 levels rose, as did the IGF-1/IGFBP-3 ratio, indicating an overall increase in IGF-1 activity. Davies et al. (26) found baseline 24-hour GH profiles in 12 pre-pubertal children with JIA and growth retardation to be the same as those seen in "short normal" children. Levels of IGF-1 and IGF BP-3 however were lower than controls. Following treatment with GH, levels of IGF-1 increased within four days and correlated with height velocity.

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