Inflammation and Growth

Growth retardation is frequently observed during chronic childhood diseases: inflammatory bowel diseases, uveitis, lupus, cystic fibrosis, and juvenile idiopathic arthritis. These diseases differ considerably in their clinical symptoms, but all involve a chronic state of inflammation. Many published clinical and experimental observations provide evidence that chronic inflammation contributes to growth retardation affecting both height and weight. This article reports the height and weight growth anomalies recorded during juvenile idiopathic arthritis (JIA). Clinical and physiopathological data highlighting the role of inflammation in causing the growth retardation observed in these patients are reported, and the various treatment options available for resolving this problem are discussed. CLINICAL DATA Height Growth and Inflammation Frédérik Still was the first to report growth retardation in children experiencing systemic forms of juvenile arthritis, well before the first use of corticosteroids as anti-inflammatory drugs. Growth retardation remains a frequent complication of this disease. Various publications have reported a short adult stature in 1% to 17% of patients with JIA. In a study of 24 children with systemic forms of JIA, 80% of the patients reached a final adult height less than their target height, and 40% had an adult height >2 SD less than the mean value for the reference population (−2 standard deviation [SD]). Growth retardation resulting in short stature occurs during the active phase of the disease and the adult height of patients appears to be closely correlated with the height attained during remission of the disease, highlighting the deleterious effects of inflammation on growth (1). In 2006, in a study of 79 patients with JIA, Souza et al (2) reported that 25% of these patients had a growth rate >2 standard deviations (−2 SD) less than the mean for chronological age. Growth rate was found to be negatively correlated with markers of inflammation: C-reactive protein concentration, erythrocyte sedimentation rate, and serum interleukin-6 (IL-6) concentration. In multivariate analysis, serum IL-6 concentration remained the best predictor of the growth rate of these patients. This effect of inflammation on growth is only partly counteracted by prolonged treatment with growth hormone (GH) continuing until the acquisition of adult height (3). Nutrition and Inflammation Nutritional problems contribute to the impairment of height growth in patients with JIA. There is frequently an imbalance between the number of calories consumed and energy requirements due to the disease: energy intake is decreased by a loss of appetite resulting from the anorexigenic effect of cytokines, pain, and sleeping problems or even due to the patient being in a depressed state. Conversely, patients with JIA have higher energy requirements than healthy children due to the higher than normal protein catabolism induced by cytokines. Protein/energy malnutrition is observed in 20% to 40% of patients with JIA. Knops et al (4) reported that basal levels of energy expenditure, expressed as a function of body mass or lean mass, were about 20% higher in patients with systemic forms of JIA than in healthy controls. In a group of 22 patients with JIA, Lofthouse et al (5) reported that 18% were found to have a weight below the third percentile. The degree of malnutrition seemed to be correlated with disease severity, and was greater for forms affecting multiple joints than for those affecting only a few joints. Finally, these patients presented abnormalities in terms of body composition: lower lean mass and lower or higher fat mass due to the effects on energy metabolism of corticosteroid treatment. PHYSIOPATHOLOGICAL DATA Low serum insulin-like growth factor (IGF)-1 concentration is the most frequently observed endocrine abnormality in patients with chronic inflammatory diseases. IGF-1 synthesis is stimulated by GH, following the binding of this hormone to its receptor on the surface of hepatocytes. The IGF-1 produced acts at a distance from the growing cartilage by stimulating the proliferation and maturation of chondrocytes, thereby inducing an increase in bone length. Furthermore, chondrocytes secrete IGF-1 locally, which then acts in a paracrine fashion to induce the same effects on the growing cartilage. The low serum IGF-1 concentrations during chronic inflammation play a key role in growth retardation. The decrease in IGF-1 levels has been reproduced experimentally in transgenic mice overproducing IL-6: these mice have high serum concentrations of IL-6 and are 30% to 50% smaller than wild-type mice (6). Several mechanisms underlie the decrease in IGF-1 concentration leading to changes in growing cartilage and growth retardation (Fig. 1): resistance to GH, as a consequence of inflammation and malnutrition mediated by a decrease in the number of GH receptors on hepatocytes and/or by changes in intracellular signalling pathways following GH binding to its receptor (7); and an increase in plasma IGF-1 clearance due to an increased proteolysis of IGF-binding protein 3 during inflammation (6). Furthermore, a direct effect of cytokines on chondrogenesis, leading to changes in growing cartilage of various degrees of reversibility, depending on the intensity and duration of cytokine exposure, has also been reported in vitro.FIGURE 1: Mechanisms involved in growth disturbances during chronic inflammation. IGF-BP = insulin-like growth factor binding protein.TREATMENT OPTIONS Nutritional problems have been clearly described in patients with JIAs, but no data have been published concerning the potential effect of adapting nutrition on the height and weight growth of these patients. New biotherapies designed to control inflammation more specifically seem to have beneficial effects on growth in children with JIA. Schmeling et al (8) reported an increase in growth rate in 7 patients treated with etanercept (which targets tumor necrosis factor-α) for 3 years. A normalisation of inflammatory markers (C-reactive protein and IL-6 levels) in the first few months of treatment was followed by an increase in IGF-1 and binding protein 3 concentrations associated with an increase in growth rate, consistent with the physiopathological data described above. Similarly, Tynjälä et al (9) compared height gain 2 years before and after antitumor necrosis factor-α treatment, and found that such treatment induced an increase in growth rate and catch-up growth. These promising results nonetheless remain dependent on the resolution of inflammation; they also require confirmation after longer periods of treatment, making it possible to evaluate the effect on the adult height of the treated patients. Two randomised control studies have demonstrated a beneficial effect of GH in children with JIA requiring corticosteroid treatment. The rapid initiation of GH treatment, 1 year after the onset of the disease, can prevent growth retardation, with the maintenance of normal height in children treated for 3 years, whereas untreated children showed a height deficit of 1.4 SD during the same period (10). Furthermore, after a mean duration of 7 years of treatment, patients with JIA treated with GH were found to have gained 1.6 SD and had a normal adult height. By contrast, the control subjects developed a height deficit of 0.7 SD during the same period, reaching a mean adult height of −3 SD (3). CONCLUSIONS Children with prolonged, severe inflammatory conditions experience problems with height and weight gain. It is important to screen for these problems early during the supervision of these patients to prevent short adult stature. The beneficial effects on growth of new, more specific biotherapies for treating inflammation are promising, but a prolonged follow-up period is required to evaluate long-term effects on adult height. The use of GH, which has been shown to be effective in children with JIA, should be evaluated for other chronic inflammatory diseases in clinical trials.