Long-Term Safety of In Utero Exposure to Anti-TNFα Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study.

OBJECTIVES: The long-term safety of exposure to anti-tumor necrosis factor (anti-TNFα) drugs during pregnancy has received little attention. We aimed to compare the relative risk of severe infections in children of mothers with inflammatory bowel disease (IBD) who were exposed to anti-TNFα drugs in utero with that of children who were not exposed to the drugs. METHODS: Retrospective multicenter cohort study. Exposed cohort: children from mothers with IBD receiving anti-TNFα medication (with or without thiopurines) at any time during pregnancy or during the 3 months before conception. Non-exposed cohort: children from mothers with IBD not treated with anti-TNFα agents or thiopurines at any time during pregnancy or the 3 months before conception. The cumulative incidence of severe infections after birth was estimated using Kaplan-Meier curves, which were compared using the log-rank test. Cox-regression analysis was performed to identify potential predictive factors for severe infections in the offspring. RESULTS: The study population comprised 841 children, of whom 388 (46%) had been exposed to anti-TNFα agents. Median follow-up after delivery was 47 months in the exposed group and 68 months in the non-exposed group. Both univariate and multivariate analysis showed the incidence rate of severe infections to be similar in non-exposed and exposed children (1.6% vs. 2.8% per person-year, hazard ratio 1.2 (95% confidence interval 0.8-1.8)). In the multivariate analysis, preterm delivery was the only variable associated with a higher risk of severe infection (2.5% (1.5-4.3)). CONCLUSIONS: In utero exposure to anti-TNFα drugs does not seem to be associated with increased short-term or long-term risk of severe infections in children.

Parathyroid hormone sensitivity in primary hyperparathyroidism and idiopathic hypercalciuria: effects on postadenylate cyclase parameters.

We performed 6-h human PTH-(1-34) infusions in 8 control subjects, 10 subjects with primary hyperparathyroidism, and 7 men with idiopathic hypercalciuria. We measured serum calcium, serum 1,25-dihydroxyvitamin D, urinary calcium, and fractional phosphate excretion. The PTH-induced rise in serum 1,25-dihydroxyvitamin-D was significantly smaller in the hyperparathyroid patients than in either the controls or the hypercalciuric patients. The rise in serum calcium was similar in all 3 groups. The hyperparathyroid subjects had higher basal fractional phosphate excretion than the other two groups. PTH failed to increase fractional phosphate excretion in the hyperparathyroid individuals, whereas there was a statistically significant increase in the other two groups. PTH was without significant effect on urinary calcium excretion in any of the three groups. There were no discernible differences between the responses of the hypercalciuric patients and those of the normal subjects. These findings suggest that while responses to PTH are normal in hypercalciuria, some hyperparathyroid patients are resistant to exogenous PTH. This resistance is limited to specific arms of the PTH response pathway and may not involve PTH receptors.

Serum vitamin D metabolites are not responsible for low turnover osteoporosis in chronic liver disease.

We measured the concentrations of vitamin D-binding protein (DBP), total 25-hydroxyvitamin D, total 1,25-dihydroxyvitamin D [1,25-(OH)2D], and free 1,25-(OH)2D in sera of 107 patients with histologically proven chronic liver disease. Bone density measurements and dynamic skeletal histomorphometry were also performed. Osteoporosis, as defined by arbitrary criteria, was found in 42 patients (39%), while no patient had osteomalacia. Serum concentrations of vitamin D-binding protein, 25-hydroxyvitamin D, total 1,25-(OH)2D, and free 1,25-(OH)2D were reduced in patients with cirrhosis, but not in the noncirrhotic patients. Bone formation rates, which were low in 55 patients (51%), were correlated with liver functions, but not with the concentrations of either vitamin D metabolite. A subgroup of 44 patients with low serum 1,25-(OH)2D concentrations and low bone formation rates failed to show an appropriate increase in serum bone Gla protein after 1,25-(OH)2D3 administration even though serum concentrations of 1,25-(OH)2D rose normally. These data suggest that the bone disease in patients with hepatic disorders is not related to the serum concentrations of vitamin D metabolites or the effect of these metabolites on osteoblast function.

Interactions between 1,25-dihydroxyvitamin D3 and vitamin D2: effects of pharmacologic doses in normal individuals.

To determine whether the administration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) affects the conversion of a pharmacologic dose of vitamin D2 to 25-hydroxyvitamin D (25OHD), 20 normal subjects received two separate doses of vitamin D2--one with and the other without the concomitant administration of 1,25(OH)2D3. Serum 1,25(OH)2D rose in response to 1,25(OH)2D3 administration and fell when vitamin D2 was given alone. Serum osteocalcin rose in response to 1,25(OH)2D3 administration. Serum 25OHD rose in response to vitamin D2 administration regardless of whether the subjects also received 1,25(OH)2D3. The data from this study in humans support the suggestion that the effects of 1,25(OH)2D3 on serum 25OHD concentrations are mediated through mechanisms other than impairment of production.

A 6-hour human parathyroid hormone (1-34) infusion protocol: studies in normal and hypoparathyroid subjects.

Parathyroid hormone (PTH)-resistant states are usually diagnosed by the failure of an acute PTH injection to elicit a rise in urinary cAMP and phosphate or, less commonly, by the failure of repeated PTH injections to raise serum calcium. We have established a 6 hour infusion of human PTH (1-34) which identifies PTH-resistant hypoparathyroid subjects on the basis of serum 1,25-dihydroxyvitamin D (1,25(OH)2D) and calcium responses. 1,25-Dihydroxyvitamin D levels increased by at least 58 pmol/liter and serum calcium by at least 0.1 mmol/liter in PTH-responsive hypoparathyroid subjects (n = 6), whereas in pseudohypoparathyroid subjects (n = 5) these levels rose by less than 22 pmol/liter and 0.06 mmol/liter respectively. The responsiveness of urinary phosphate excretion, expressed as the renal threshold phosphate concentration (TmPO4/GFR), to PTH also clearly separated the pseudohypoparathyroid patients from the other subjects. Differences in urinary calcium responses were observed though this parameter was less reliable in the identification of individual PTH-resistant or PTH-sensitive hypoparathyroid patients. Nephrogenous cAMP did not discriminate between groups when this protocol was used. This test has the potential to facilitate and extend the classification of PTH-resistant states.

Bioactive parathyroid hormone in the rat: effects of calcium and calcitriol.

Bioactive PTH was measured in Wistar rats under a variety of experimental conditions. The mean activity in normal rat sera was 0.17 +/- 0.12 ng/ml (expressed in terms of bovine PTH 1-34). Sera from animals reared on a vitamin D deficient diet showed a mean value of 0.46 +/- 0.24 ng/ml (P less than 0.01), whereas sera from animals with 1,25-dihydroxyvitamin D (1,25(OH)2D) deficiency had a mean activity of 0.62 +/- 0.23 ng/ml (P less than 0.01). Dietary calcium deficiency also resulted in high serum PTH levels (0.71 +/- 0.34 ng/ml, P less than 0.01) in spite of marked elevations of serum 1,25(OH)2D concentrations in these animals. A significant negative correlation was noted between serum calcium and bioactive PTH. Calcium infusions into hypocalcemic, vitamin D-deficient rats caused a fall in serum bioactive PTH concentrations to a mean of 13% of control values within 10 min. Intraperitoneal administration of 1,25(OH)2D3 to hypocalcemic, 1,25(OH)2D-deficient rats did not suppress serum bioactive PTH concentrations after 30 or 60 min even though serum 1,25(OH)2D concentrations were greater than 900 pmol/liter in each animal at these time points. To our knowledge, this is the first study using PTH bioassays for physiological experiments in rats.

Vitamin D conversion by sarcoid lymph node homogenate.

Recent studies suggest that hypercalcemia of sarcoidosis is due to high blood concentrations of calcitriol and that this compound may be synthesized at an extra-renal site. We report that sarcoid lymph node homogenate metabolized calcifediol to a substance indistinguishable from calcitriol, whereas six nonsarcoid lymph nodes failed to produce this compound.

Vitamin D metabolism in nephrotic rats.

Vitamin D metabolites were measured in sera of normal, vitamin D deficient and nonazotemic nephrotic rats. The concentrations of all metabolites were reduced in nephrotic and vitamin D deficient animals although 1,25-dihydroxyvitamin D values remained relatively normal in the nephrotic group. Twenty-four hours after the intravenous injection of tritiated 25-hydroxycholecalciferol, approximately 34% of the injected radioactivity appeared in the urine of the nephrotic animals compared with 0.4% in the controls. In extracts from nephrotic sera subjected to high performance liquid chromatography, the percentage of radioactive counts comigrating with 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol was significantly increased. The various metabolites were present in urine in approximately the same ratios as in serum. Dynamic histomorphometry of tibial metaphyses showed no abnormality. Urinary losses of vitamin D metabolites constitute the major cause for low serum values in nephrotic rats. The apparent synthetic rates are not impaired.

Effect of aluminum on normal and uremic rats: tissue distribution, vitamin D metabolites, and quantitative bone histology.

The effects of intraperitoneal aluminum chloride (1.5 mg aluminum/kg/day for 9 weeks) were studied in normal and uremic rats. Parameters measured included tissue aluminum, serum vitamin D metabolites, and quantitative bone histology. Aluminum administration increased tissue concentrations of this metal in uremic and nonuremic animals. Bone aluminum concentrations were higher in uremic rats (121 +/- 27 mg/kg compared to 47 +/- 4), whereas liver values were higher in the nonuremic group (175 +/- 47 mg/kg compared to 100 +/- 36). Serum concentrations of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D were reduced in uremia, but aluminum was without apparent effect on any vitamin D metabolite. Aluminum, in the doses administered, caused no skeletal changes in nonuremic animals. Some uremic, non-aluminum-treated rats developed osteomalacia and marrow fibrosis. However, osteomalacia was more severe and the osteoclast count was higher in the uremic, aluminum-treated rats. In this group of animals the mineral apposition rate was reduced at the metaphyseal endosteum but increased at the periosteum, indicating different control mechanisms at the two sites.

Vitamin D metabolism in hypophosphatemic rickets.

Vitamin D metabolites were measured in 21 patients with hypophosphatemic osteomalacia of juvenile onset. In eight patients who had not received any antirachitic treatment, serum 25-hydroxyvitamin D(25-OH-D) and 1,25-dihydroxyvitamin D (1,25-[OH]2D) values were normal, whereas serum 24,25-dihydroxyvitamin D (24,25-[OH]2D) values were lower than in normal subjects. In 13 patients who were receiving ergocalciferol and oral elemental phosphorus, serum 25-OH-D and 24,25-(OH)2D concentrations were elevated and serum 1,25-(OH)2D values were low. The findings in untreated patients supported the hypothesis that vitamin D metabolism is abnormal in hypophosphatemic rickets/osteomalacia. The reduction of serum 1,25-(OH)2D levels with ergocalciferol and phosphate therapy gives further support to a therapeutic role for 1,25-(OH)2D in this disorder.

Vitamin D metabolites and their relationship to azotaemic osteodystrophy.

Bone biopsies were performed and serum concentrations of vitamin D metabolites were measured in twenty-four patients with chronic renal failure. The concentrations of three metabolites--25-dihydroxyvitamin D (25-OHD), 24,25-dihydroxyvitamin D (24,25-OH2D) and 1,25-dihydroxyvitamin D (1,25-OH2D)--were significantly lower in uraemic than in normal sera. There was a positive correlation between serum 24,25-OH2D and serum 25-OHD, whereas serum 1,25-OH2D values, which were independent of those of the other vitamin D metabolites, were negatively correlated with serum creatinine and serum inorganic phosphate. The two major skeletal lesions, osteomalacia and parathyroid osteopathy, while coexisting in many patients, varied independently in relation to their severity and were correlated with different vitamin D metabolites. The severity of osteomalacia was negatively correlated with the serum concentrations of 25-OHD and 24,25-OH2D while th severity of parathyroid osteopathy was negatively correlated with serum 1,25-OH2D values. To our knowledge these are the first systematic studies correlating skeletal histology with dihydroxylated vitamin D metabolites in renal failure in man.

A simplified assay for dihydroxylated vitamin D metabolites in human serum: application to hyper- and hypovitaminosis D.

We describe a simplified assay for 24,25-and 1.25-dihydroxyvitamin D in human serum. It involves two preparative steps, and normal chick intestine is used in preparing cytosol-binding protein. Our results for 24,25-dihydroxyvitamin D include a reference interval of 2.9--16 nmol/L (1.2--6.7 microgram/L), a mean of 6.7 nmol/L (2.8 microgram/L), an intra-assay CV of 11%, and an interassay CV of 22%. For 1,25-dihydroxyvitamin D, these data were 29--168 pmol/L (12--70 ng/L), 86 pmol/L (36 ng/L), 12%, and 22%, respectively. In hypoparathyroid patients with vitamin D intoxication, mean concentrations of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D in serum were significantly above normal; the 1,25-dihydroxyvitamin D concentrations were significantly below normal. Patients with malabsorption and/or post-gastrectomy states had significantly subnormal values for both 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D in serum, and there was a significantly negative correlation between each of these biochemical values and the severity of osteomalacia. We also discuss cost effectiveness of assaying vitamin D metabolites in human serum.