Susan H. Allen

Bone metabolism in children with asthmatreated with inhaled beclomethasone dipropionate

Previous studies have shown that inhaled corticosteroids can affect bone metabolism in adults. A study to assess the effect of inhaled beclomethasone, 300 to 800 micrograms/day for at least 6 months (mean 25 months), was therefore undertaken in children. In part 1 of the study, 18 children with asthma, aged 4 to 17 years (mean 10.1 years), were compared with an age- and sex-matched group of children with asthma not treated with corticosteroids. In part 2, eight more pairs were compared. Comparisons were also made with 61 healthy children. Bone mineral density measured by radiographic absorptiometry, and bone mineral content measured by single-photon absorptiometry and by dual-energy x-ray absorptiometry, showed no significant differences. Serum levels of calcium, magnesium, zinc, total alkaline phosphatase, bone specific alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D also showed no differences. The activity of tartrate-resistant acid phosphatase, a marker of bone resorption, was significantly lower in the beclomethasone group than in both the asthma control and the normal control groups, but urine calcium excretion did not differ. Patients with asthma had lower serum osteocalcin and higher serum copper levels than control subjects without asthma, but treatment with beclomethasone did not affect these values. We conclude that inhaled beclomethasone (up to 800 micrograms/day) does not reduce bone mineralization or increase bone resorption. Effects on bone formation were difficult to assess because asthma per se caused a significant reduction in osteocalcin, a sensitive marker of bone formation.

Vitamin D metabolism and bone mineralization in children with juvenile rheumatoid arthritis

OBJECTIVE To examine bone mineralization and bone mineral content in a cross-sectional population of children with juvenile rheumatoid arthritis (JRA). METHODS Bone mineral content was measured by single-photon absorptiometry in 44 children with JRA and 37 control children. Serum concentrations of minerals, vitamin D, parathyroid hormone, osteocalcin, bone alkaline phosphatase, and tartrate-resistant acid phosphatase, and urinary concentrations of minerals, were determined. RESULTS Bone mineral content was decreased in children with JRA. Significantly lower concentrations of osteocalcin (7.4 +/- 3.4 vs 12.5 +/- 2.5 micrograms/L) and bone alkaline phosphatase (78.8 +/- 36.4 vs 123.0 +/- 46.0 IU/L) suggested reduced bone formation; lower levels of tartrate-resistant acid phosphatase (10.3 +/- 4.1 vs 14.4 +/- 5.8 IU/L) and a lower urinary calcium/creatinine ratio (0.07 +/- 0.06 vs 0.12 +/- 0.09) suggested decreased bone resorption. The serum calcium concentration was significantly lower (9.3 +/- 1.0 vs 10.0 +/- 0.4 mg/dl), as was the parathyroid hormone concentration (19.8 +/- 8.6 vs 26.7 +/- 9.3 ng/L); 1,25-dihydroxyvitamin D values (30.1 +/- 10.5 vs 30.4 +/- 9.3 pg/ml) were normal. CONCLUSION These data suggest that decreased mineralization in JRA is related to low bone turnover; parathyroid hormone and 1,25-dihydroxyvitamin D levels may be inappropriately normal for the decreased serum calcium concentration in children with JRA.

Review : Prolactin: a stimulator of disease activity in systemic lupus erythematosus

It is accepted that estrogen and testosterone have the potential to affect the severity of autoimmunity in animal models’ and humans with systemic lupus erythematosus (SLE)2,3. More recently, the anterior pituitary hormone, prolactin, has been shown to have immune-stimulating propertieS4 and high concentrations of prolactin were associated with accelerated disease in Fez I hybrid New Zealand Black X New Zealand White (NZB/NZW) mice, which develop a lupus-like disorders. When NZB/NZW females were made chronically hyperprolactinemic by pituitary transplantation, the animals died prematurely with autoimmune renal disease. In contrast, treatment with the prolactin-suppressing drug, bromocriptine, was beneficial6. Hyperprolactinemia has also been linked to human lupus. Abnormal elevations of serum prolactin have been reported in 22% of women with SLE , in pregnant women with lupus flares8 and in men with SLE9. The authors recently evaluated four women with chronic hyperprolactinemia who also developed SLE: in two instances, lupus appeared I or 6 months after bromocriptine therapy was stoppedlo. This article will review the effects of two patterns of hyperprolactinemia: prolonged, pituitary implant-induced prolactin elevation and episodic ’physiologic’ hyperprolactinemia in the NZB/NZW mouse model of lupus. The authors will discuss the reported associations between SLE and hyperprolactinemia, and describe recent experience with chronically hyperprolactinemic women who have developed SLE. If hyperprolactinemia is deleterious, are normal levels of prolactin harmful in SLE? In this review, the proposal will be considered that physiological concentrations of circulating prolactin, falling within the accepted range of normal values, chronically promote disease activity in the SLE patient. Long-term use of a prolactin-suppressive drug would therefore be a reasonable form of adjunct treatment of SLE. Preliminary analyses of a recent therapeutic trial have advanced this supposition. The authors found that bromocriptine, which inhibits pituitary secretion of prolactin, was associated with remission in selected patients with active SLE 11. z

Prolactin levels and antinuclear antibody profiles in women tested for connective tissue disease.

Hyperprolactinemia has been reported in some patients with active systemic lupus erythe matosus (SLE). To determine if there was an association between selected autoantibodies and hyperprolactinemia, we assayed prolactin concentrations in sera from women sub mitted to a reference antinuclear antibody laboratory. Autoantibody-positive samples were separated into groups that contained antibodies to double-stranded DNA (anti-DNA), anti bodies to SSA/Ro (anti-SSA/Ro), or antibodies to both SSA/Ro and SSB/La (anti-SSA/Ro- SSB/La). Results were compared with autoantibody-negative sera from age-matched women, submitted to the same laboratory. We also compared the study groups with a separate cohort of 84 healthy women who were not referred for autoantibody testing. Elevated prolactin levels were clustered in 20% of sera from anti-DNA-positive women ≤50 years of age. Twenty-one percent of anti-SSA/Ro-SSB/La-positive women < 50 years of age were hyperprolactinemic. Four of the 15 hyperprolactinemic women identified in this survey had no known cause of elevated prolactin. In the other 11 individuals, secondary causes such as hypothyroidism, pregnancy, chronic renal failure, and medications may have accounted for high serum prolactin values. We also examined sera by Western blot, to determine if immunoblot patterns were associated with elevated serum prolactin concentra tions. The hyperprolactinemic sera yielded novel bands migrating at 70 kd, 32 kd, and 16.5 kd. This study confirmed the reported associations of hyperprolactinemia with SLE and Sjögrens syndrome. Multiple factors appeared to contribute to elevated serum prolactin levels in women with connective tissue diseases, and the presence of hyperprolactinemia was related to unique findings on immunoblot analysis.Sjögrens syndrome (SS) is a chronic autoimmune rheumatic disorder characterized by lymphocytic infiltration and destruction of exocrine glands, mainly of salivary and lacrimal glands, leading to dryness of mouth and eyes. It can occur either alone (primary SS) or in association with almost every systemic autoimmune rheumatic SS). Usually, SS patients have slowly progressive disease confined in exocrine glands, however, in approximately one third of primary SS patients the disorder presents a systemic and progressive course with involvement of diverse extraglandular sites and in a small but significant number of patients with lymphoid neoplasia development. Although the aetiology of SS remains unknown, chronic immune system stimulation is thought to play a central role in the pathogenesis of the disorder, as illustrated by several indices of immunological hyperactivity, including various autoantibodies, polyclonal hypergammaglobulinemia and circulating paraproteins. To date, treatment of SS remains largely empirical and symptomatic, and no clinical trial has been proved capable to change the course of the disease. Hydroxychloroquine has been successfully applied for the treatment of arthralgias, myalgias and general constitutive symptoms of SS patients. In an initial small open study, hydroxychloroquine administration has been shown to improve features of immunological hyperreactivity, such as hypergammaglobulinaemia and autoantibody levels. However, large prospective double-blind studies are still needed to assess the long-term efficacy of hydroxychloroquine in preventing extraglandular involvement and lymphoma development in primary SS patients.

Prolactin and autoimmune disease

A number of reports have shown that PRL is an immune-stimulating hormone that is capable of stimulating organ-specific inflammatory disease in humans. More recently, hyperprolactinemia has been associated with the active phase of the immune-complex-mediated autoimmune disease, systemic lupus erythematosus. The theory that PRL contributes substantially to disease activity was upheld in the NZB/W mouse model of spontaneous, hormone-sensitive lupus. Implanted pituitary glands resulted in hyperprolactinemia, accelerated proteinuria, high levels of circulating IgG, and premature death. Therapeutic studies with NZB/W mice, as well as anecdotal evidence from a small number of patients, have provided evidence that PRL suppressive therapy may be beneficial in selected cases of autoimmune disease.

Bone Mineral Metabolism in Children with Juvenile Rheumatoid Arthritis

Osteopenia has emerged as a major determinant of the outcome of children with juvenile rheumatoid arthritis. Although vertebral compression fractures and fractures of long bones were recognized historically as important clinical developments in the course of disease, a decrease in skeletal mass could only be quantitated and documented early in disease by the recent introduction of bone absorptiometry. This article is limited to recent data from studies on osteopenia in juvenile rheumatoid arthritis and suggests directions of future research that have relevance to current unanswered questions in prevention or management.

Calcinosis and Metastatic Calcification due to Vitamin D Intoxication

Vitamin D, a fat-soluble vitamin, can be associated with significant morbidity when prescribed in large doses. We describe a hypoparathyroid patient with vitamin D intoxication who developed painful periarticular calcinosis, nephrocalcinosis with hypertension and chronic renal failure in addition to band keratopathy and hearing loss. He was treated with combination therapy including prednisone, phosphate-binding antacid, phenytoin and disodium etidronate. After 20 months of follow-up there was a significant reduction of periarticular calcinosis, but no improvement in renal function, band keratopathy or hearing loss and possible calcification of the ossicles. The clinicopathologic features of metastatic calcification and the various treatment modalities are reviewed.

Prolactin and Autoimmunity: Influences of Prolactin in Systemic Lupus Erythematosus

The autoimmune disease, systemic lupus erythematosus (SLE), is incurable, and individuals with this illness are at risk of severe and potentially fatal involvement of the central nervous system and kidneys.1,2 SLE occurs most commonly in women of childbearing age, and evidence has suggested that this disease is influenced by reproductive hormones.3 Recent studies in this laboratory have employed a hormone-sensitive murine model of SLE, the NZB X NZW (B/W) mouse,4 to investigate the role of the lactotrope, prolactin,5,6 in spontaneously occurring autoimmune disease. This report will summarize our findings in groups of female B/W mice made hyperprolactinemic or, conversely, treated with bromocriptine, an inhibitor of prolactin secretion.7