Growth hormone treatment in children with rheumatic disease, corticosteroid induced growth retardation, and osteopenia.

BACKGROUND: In children with severe rheumatic disease (RD), treatment with corticosteroids (CS) is frequently needed and growth retardation and osteopenia may develop. A beneficial effect of human growth hormone (hGH) has been reported but mostly in trials without a control group. AIMS: To study the effect of hGH on growth, bone mineral density (BMD), and body composition, taking the disease activity and CS use into account. METHODS: Randomised controlled trial on 17 prepubertal RD patients with growth retardation and/or decreased BMD. The hGH group (n = 10) received treatment with hGH 4 IU/m2/day (approximately 0.045 mg/kg/day) during two years. The controls (n = 7) received no GH treatment. RESULTS: During the two year study period the disease activity, and use of CS and methotrexate (MTX) did not differ between the groups. There was a significant mean increase in height standard deviation score (HSDS) in the hGH group (0.42+/-0.16 SDS) and a non-significant decrease in the controls (-0.18+/-0.11 SDS). Change in BMD did not differ significantly between the groups, although the increase in BMD for lumbar spine within the hGH group was significant. Lean body mass improved significantly in the hGH group compared to controls (0.64+/-0.19 SDS versus -0.20+/-0.17 SDS), while the decrease in percentage fat was not significant. CONCLUSIONS: There was a significant effect of hGH on growth and lean body mass, but a longer duration of treatment might be necessary to evaluate the effect of hGH on BMD.

Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D.

OBJECTIVES: The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency. METHODS: The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced. RESULTS: Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations. CONCLUSIONS: Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.

Effects of sulfasalazine treatment on serum immunoglobulin levels in children with juvenile chronic arthritis.

This article describes the effects of sulfasalazine (SSZ) treatment on serum immunoglobulin (Ig) levels in 6 children with oligoarticular- or polyarticular onset juvenile chronic arthritis (JCA). None of the children who developed dysimmunoglobulinemia during treatment showed clinical symptoms of this adverse event, in particular none developed severe infections. All patients regained normal immunoglobulin levels after discontinuing SSZ treatment. One patient with a partial IgA deficiency at the start of SSZ treatment showed a slow increase in the IgA level during treatment. During follow-up (4-6 years), one patient spontaneously developed a dysimmunoglobulinemia and one patient developed diabetes mellitus. Based on these case reports and review of the literature we advocate monitoring of serum immunoglobulin levels while on SSZ treatment.

Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group.

OBJECTIVE: To assess the efficacy, tolerability, and safety of sulfasalazine (SSZ) in the treatment of juvenile chronic arthritis (JCA). METHODS: We conducted a 24-week randomized, placebo-controlled, double-blind, multicenter study of patients with active JCA of both oligoarticular and polyarticular onset. Patients were treated with a dosage of 50 mg/kg/day of SSZ (maximum 2,000 mg/day) or placebo. The efficacy variables were joint scores, physician's, parents', and patient's overall assessments, and laboratory parameters of inflammation. RESULTS: Of the 69 patients enrolled, 52 (75%) completed the trial. Six patients (18%) withdrew from the placebo group, and 11 (31%) withdrew from the SSZ group (P = 0.18). In the intention-to-treat analysis of end point efficacy, between-group differences were significant for the overall articular severity score (P = 0.02), all global assessments (P = 0.01), and the laboratory parameters (P < 0.001). Adverse events occurred more frequently in the SSZ group and were the main reason for withdrawal (P < 0.001), but in all instances, these events were transient or reversible upon cessation of treatment. CONCLUSION: The results of this first placebo-controlled study show that SSZ is effective and safe in the treatment of children with oligoarticular- and polyarticular-onset JCA, although it was not well tolerated in one-third of the patients.

Juvenile-onset mixed connective tissue disease: longitudinal follow-up.

To establish the symptoms and clinical course of juvenile-onset mixed connective tissue disease, we studied 14 patients, classified according the criteria of Kasukawa et al. The patient records were studied retrospectively and all patients were examined in a 1-day follow-up program. Systemic lupus erythematosus and polymyositis/dermatomyositis-like symptoms disappeared in time, whereas scleroderma-like symptoms (such as in the Raynaud phenomenon) and joint abnormalities persisted. Extensive limitation of joint function was found in four patients. At the time of follow-up, no active renal disease was found. Thrombocytopenia was still present in one of the three patients who had had this feature. All patients had abnormalities of esophageal motility. Long-term corticosteroid treatment was associated with aseptic bone necrosis in three patients and growth retardation in one. We conclude that the Kasukawa criteria are easy to apply to children, and that juvenile-onset mixed connective tissue disease has many similarities to the adult form of the disease.

Protein intake can not be estimated from urinary urea excretion.

We assessed the relationship between protein intake (calculated from a 3-day prospective dietary diary) and 24-h urinary urea excretion in 37 children with chronic renal failure. Protein intake was not restricted during the investigation period. The 24-h urinary urea excretion correlated poorly with the protein intake estimated from the dietary diary (r = 0.58). We conclude that although it is common practice to assess compliance with a protein-restricted diet in children with chronic renal failure with a dietary diary and 24-h urinary urea excretion, the value of this assessment is questionable.

[Vasculitis in childhood]. / Vasculitis op de kinderleeftijd.

Vasculitis, defined as an inflammation of blood vessels resulting in ischemic tissue lesions, is a feature of many different diseases and symptoms in childhood. A uniform classification based on characteristic clinical symptoms and histopathological signs is as yet not possible. Most vasculitic syndromes are rarely seen in childhood. This review deals with the more frequently encountered vasculitic syndromes such as polyarteritis nodosa, Kawasaki disease and Henoch-Schönlein purpura. A survey of clinical and histopathological findings as well as recent insights in the pathogenesis and pathophysiology will be given.

Stable isotope dilution analysis of cystine in granulocyte suspensions as cysteine: a powerful method for the diagnosis, the follow-up, and treatment of patients with cystinosis.

A stable isotope dilution method was developed for the determination of cystine in granulocytes. Granulocytes were isolated from blood samples of treated cystinosis patients. Cystine in the granulocyte suspension was decoupled from proteins and converted to cysteine by treatment with a tri-butyl phosphine solution. Tertiary butyldimethyl silyl derivatives were prepared and analyzed by gas chromatography/mass spectrometry. Selective ion monitoring was carried out at m/z 304.3 (M-159 and m/z 406.4 (M-57) for the natural, and at m/z 306.3 and 408.4 for the labelled compound. [3,3,3',3'-2H]-DL-cystine was used as internal standard for the isotope dilution analysis. Concentrations of cystine in granulocytes could be accurately measured. There was a distinct difference in cystine concentrations in healthy individuals and treated patients.

Renal handling of technetium-99m DMSA: evidence for glomerular filtration and peritubular uptake.

The finding of an enhanced excretion of [99mTc]dimercaptosuccinic acid (DMSA) in patients with tubular reabsorption disorders prompted us to investigate the role of filtration in the renal handling of [99mTc]DMSA. Our studies in human serum indicated that binding to serum proteins was approximately 90%. Chromatography of human urine and studies in rats showed that the complex was excreted unaltered into the urine. Renal extraction of [99mTc]DMSA in a human volunteer was 5.8%. Continuous infusion of [99mTc]DMSA in 13 individuals with normal renal function gave the following results (mean +/- s.d.): plasma clearance of [99mTc]DMSA 34 +/- 4 ml/min, urinary clearance of [99mTc]DMSA 12 +/- 3 ml/min. The calculated filtered load of [99mTc]DMSA closely resembled the urinary clearance, whereas the plasma clearance was about three times faster. This indicates that peritubular uptake accounts for approximately 65% and filtration for approximately 35% of the renal handling of [99mTc]DMSA.

Do circulating factors play a role in the pathogenesis of minimal change nephrotic syndrome?

This review examines the studies which have been undertaken to test the hypothesis that minimal change nephrotic syndrome of childhood (MCNS) is a primary immune disorder and that there is altered T-cell function which results in release of a circulating factor. This factor alters glomerular permeability, perhaps by modifying charge sites in the glomerular capillary bed, and results in selective proteinuria. The abnormalities in immune function observed in MCNS are summarized, as are the studies of circulating factors which have been identified. Although some agents have been shown to alter capillary permeability, the unequivocal demonstration of such a factor causing selective proteinuria in vivo, either directly or indirectly, is lacking. The question is raised whether intrarenal release or activation of mediators of altered permeability, rather than the systemic release of such factors, may be important in the pathogenesis of MCNS.

Loss of glomerular polyanion in vitro induced by mononuclear blood cells from patients with minimal-change nephrotic syndrome.

Peripheral mononuclear blood cells isolated from nephrotic subjects with minimal-change nephrotic syndrome (selective proteinuria greater than 3.5 g/24 h) or various other forms of glomerulonephritis (non-selective proteinuria greater than 3.5 g/24 h) were stimulated with concanavalin A and cultured for 20 h in the presence of kidney tissue under standard conditions. Identical cultures were developed with phosphate-buffered saline from normal control donors. Triplicate cultures of each subject (3 X 10(6) cells/ml) were incubated with or without 5, 10, or 20 micrograms/ml concanavalin A per milliliter serum-free tissue culture medium upon cryostat sections from normal rat kidney. The cells were subsequently removed, and the tissue sections were washed and stained for sialoprotein using the colloidal iron method and evaluated for stainability of glomerular polyanion using light microscopy. The results show that peripheral mononuclear blood cells from subjects with minimal-change nephrotic syndrome had affected glomerular polyanion in vitro during incubation with kidney tissue in a significantly (p less than or equal to 0.005) higher number of cases (15/17) as compared with the number of glomerulonephritis patients who scored positive in 4 out of 14 cases, whereas this was the case in 3 out of 18 cases of the normal donors. It is concluded that stimulated cellular immune reactivity of peripheral mononuclear blood cells from subjects with minimal-change nephrotic syndrome in vitro is associated with the potential impairment in vitro of an important part of the glomerular filtration barrier. Since this cellular activity occurred to a significant lesser extent in other nephrotic subjects, this response is not related to the nephrotic state per se.

Is the relative 99mTc-DMSA clearance a useful marker of proximal tubular dysfunction?

The clearance of 125I-sodium iothalamate, 131I-sodium hippurate, 99mTc-DMSA, and beta 2-microglobulin were determined in 20 patients with proven or suspected proximal tubular dysfunction and in 18 control patients with various renal diseases. A clear distinction in the relative 99mTc-DMSA clearance was observed between patients with proximal tubulopathy (14%-35%) and control patients (less than 14%). A similar difference between the two groups was found in the relative beta 2-microglobulin clearance. Nine patients with proximal tubulopathy showed an elevated filtration fraction versus only two control patients. The renal handling of 99mTc-DMSA seems to be an indicator of proximal tubular function.

Vascular permeability increasing factor (VPF) in IgA nephropathy.

Peripheral blood mononuclear cells (PBC) from non-nephrotic and nephrotic patients with different glomerulopathies were tested for their potential to produce vascular permeability increasing factor (VPF) after stimulation with Concanavalin-A (Con-A) in vitro. Supernatants from cultures of PBC from patients with IgA nephropathy were injected intradermally into the skins of normal Wistar rats which were given Evans blue dye solution intravenously. The mean extravasation of dye after 60 minutes was taken as a standard for the induction of local vascular permeability. Using a routine vascular permeability assay based on this principle similar studies were done with supernatants from cultures of PBC from nephrotic subjects with minimal change disease (MCD), or membranous nephropathy (MGN) and from healthy donors. The results show that cultures of PBC from non-nephrotic subjects with IgA nephropathy as well as from nephrotic MCD patients produced VPF in their supernatants whereas lymphocytes from nephrotic MGN subjects or normal donors did not. It is concluded that the production of VPF in stimulated PBC cultures from patients with IgA nephropathy or MCD might reflect altered T-cell function in these diseases, and that there is no direct relationship between VPF production and increased glomerular permeability.