Introduction: This study evaluated the effect of oral alendronate on the BMD of adult patients with osteogenesis imperfecta.Materials and Methods: We carried out a 3-year, randomized, double-blind, placebo-controlled trial of oral alendronate in 64 adult patients with osteogenesis imperfecta. The primary endpoint was the difference between the groups in the mean percent change in lumbar spine BMD at 3 years. Secondary outcomes included changes in BMD of total hip, vertebral and peripheral fracture incidence, pain, hearing loss, and bone turnover biochemical markers. Patients were treated daily with either placebo or 10 mg alendronate. All received 1 g of calcium and 800 IU of vitamin D daily.Results: The mean +/- SD increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Hip BMD increased in the alendronate group by 3.3 +/- 0.5% (p = 0.001) and decreased in the placebo group by 0.3 +/- 0.6%. The sample size was not sufficient to determine an effect of alendronate on fracture rate. A significant increase of the pain score was noted in the alendronate group (p = 0.04) in the intent-to-treat analysis but not in the per protocol analysis. There was no change in hearing in either group. Bone resorption and formation biochemical markers were significantly decreased in the alendronate group (p < 0.001). There were no differences in severe adverse effects between the groups, but there was an increase in nonsevere upper gastrointestinal effects in the alendronate group (p = 0.003).Conclusions: Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta. More studies are needed to evaluate an effect on the fracture rate.

This review focuses on recent advances and new hypothesis in the understanding of the T and dendritic cells contribution to the pathogenesis of idiopathic inflammatory myopathies (IIMs), especially polymyositis (PM) and dermatomyositis (DM). The new data show that non-specific amplification of muscle inflammation by T lymphocyte and dendritic cells may result from the local production of cytokines and chemokines. Synergistic interactions between these factors explain some of the clinical features. The potent role of these molecules suggests their potential for therapeutic manipulation using specific inhibitors.

OBJECTIVE To evaluate the effect of tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, and their respective inhibitors the p75 TNFalpha soluble receptor (sTNFR) and the type II sIL1betaR (sIL1RII) on whole muscle and isolated myoblast activation. METHODS Normal muscle samples were stimulated for 7 days with TNFalpha alone or in combination with IL1beta, and myoblasts from these samples for 48 hours. IL6 production was measured by ELISA. Nuclear translocation of NF-kappaB was analysed by immunofluorescent staining and class I MHC expression by FACS. RESULTS TNFalpha and IL1beta induced IL6 production by normal muscle samples and myoblasts, the action of TNFalpha being more potent on muscle samples. Their soluble receptors (1 microg/ml) decreased this production. Suboptimal concentrations of TNFalpha and IL1beta induced NF-kappaB translocation. sTNFR markedly down regulated TNFalpha-induced translocation while sIL1RII was less potent on IL1beta-induced activation. NF-kappaB translocation induced by the combination of optimal concentrations of TNFalpha and IL1beta was completely inhibited by their soluble receptors. TNFalpha and to a lesser extent IL1beta induced class I MHC expression by myoblasts and this effect was completely inhibited by their respective soluble receptors. CONCLUSION These results suggest that TNFalpha and IL1beta should be targeted for myositis treatment.

OBJECTIVE:To clarify the involvement of dendritic cells (DCs), chemokines, and proinflammatory Th1 cytokines in the pathogenesis of the chronic muscle diseases dermatomyositis (DM) and polymyositis (PM).METHODS:We characterized by immunohistochemistry the DC subsets and their interaction with cells producing chemokines and the Th1 cytokines interleukin-17 (IL-17) and interferon-gamma (IFNgamma). Immature and mature DCs were defined by the expression of CD1a and DC-LAMP/CD83, respectively.RESULTS:Immature DCs were mainly detected in lymphocytic infiltrates in DM and PM muscle tissue samples. Mature DCs were detected in perivascular infiltrates and surrounded muscle fibers. IL-17-positive and IFNgamma-positive cells were also observed in perivascular infiltrates in both cases. We then focused on the expression of the CCL20/CCR6 chemokine/receptor complex, which controls immature DC migration, and on the expression of the CCL19/CCR7 and CCL21/CCR7 chemokine/receptor complexes, which control mature DC migration. CCL20 and CCR6 colocalized in lymphocytic infiltrates in DM and PM samples. CCL21 was rarely observed in DM samples and never observed in PM samples. CCL19- and CCR7-expressing cells were absent in both tissues.CONCLUSION:The close association between CCL20/CCR6 and immature DCs suggests the contribution of CCL20 to CCR6+ immature DC homing. Detection of mature DCs in DM and PM muscle tissue samples despite the lack of CCL19 and CCR7 is evidence for a local maturation of DCs in inflammatory muscle tissue without lymphoid organ organization.

Objective. To clarify the association between parvovirus B19 and myositis.Methods. Biopsy samples of muscle from eight patients with inflammatory myopathies were studied for the presence of B19 DNA by polymerase chain reaction. Expression of VP1 and VP2 capsid proteins was evaluated by immunohistochemistry. Interleukin 6 (IL-6) production was measured in the supernatant of myoblasts following incubation with parvovirus B19.Results. In seven samples, detection of B19 DNA was negative. The expression of VP1 and VP2 capsid proteins was not observed by immunohistochemistry. In one patient, detection was transiently positive but became negative despite a flare-up of muscle disease. In vitro, parvovirus B19 was not able to induce IL-6 production by myoblasts.Conclusion. Our results do not support the direct implication of parvovirus B19 in the pathogenesis of myositis.

We studied the production of interleukin (IL)-6 and CCL20/macrophage inflammatory protein-3α (MIP-3α) by human myoblasts and muscle samples in response to IL-17 alone or in combination with IL-1β. Both IL-17 and IL-1β induced IL-6 production by normal myoblasts and muscle samples. IL-17 had no effect on CCL20 production by myoblasts. Combination of IL-17 and IL-1β further increased IL-6 and CCL20 production by muscle samples but not that of CK. IL-17 induced also HLA class I, C-Fos, nuclear factor κB (NF-κB) and C-Jun expression by myoblasts but not that of HLA class II, CD40, vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). Finally, immunostaining of dermatomyositis (DM) and polymyositis (PM) muscle biopsies showed IL-17 and CCL20 expression. Our study shows that low levels of cytokines produced by T cells (IL-17) and monocytes (IL-1β) can act in combination on skeletal myoblasts and muscle tissue.

Objectives: To evaluate the usefulness of combination treatment with cytokine inhibitors.Methods: A simplified model was set up to evaluate the effect of tumour necrosis factor alpha (TNFalpha) soluble receptors (sTNFR) used alone and in combination with soluble interleukin 1 receptor (sIL1R) and sIL17R on the production of markers of inflammation (IL6), of migration of dendritic cells (macrophage inhibitory protein-3alpha (MIP-3alpha)), and of matrix synthesis (C-propeptide of type 1 collagen (P1CP)). Synoviocytes were stimulated with supernatants of activated peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA). Soluble receptors (sR) were preincubated at 1 mug/ml alone or in combination with the supernatants before addition to RA synoviocytes. IL6, MIP-3alpha, and P1CP production was measured by enzyme linked immunosorbent assay (ELISA) in 48 hour synoviocyte supernatants.Results: IL6 production decreased by 16% with sTNFR alone compared with no sTNFR (p<0.001) and by 41% with the combination of the three sR (p<0.001). MIP-3alpha production decreased by 77% with sTNFR alone compared with no sTNFR (p<0.001) and by 98% with the combination of the three sR (p<0.001). In the presence of sTNFR alone, P1CP production increased by 25% compared with no sR (p<0.01). The combination of the three sR increased P1CP production by 48% (p<0.0 1).Conclusion: The effect of sTNFR on IL6, MIP-3a, and PICP production by RA synoviocytes stimulated by activated PBMC supernatants was further enhanced when combined with sIL1R and sIL17R.

L’ostéogenèse imparfaite est une maladie génétique qui regroupe un ensemble d’affections de gravité variable toutes caractérisées par une fragilité osseuse. Celle-ci entraîne des fractures et des déformations du squelette pour des traumatismes minimes. Sa classification a été récemment complétée tant sur le plan clinique qu’histomorphométrique. Souvent facile dans la petite enfance, son diagnostic n’est parfois établi qu’à l’âge adulte. Sa prise en charge multidisciplinaire est indispensable tout au long de la vie. Le traitement par pamidronate chez l’enfant reste le mieux étudié et son intérêt établi. D’autres bisphosphonates sont en cours d’évaluation, en particulier chez l’adulte. La prévention d’une insuffisance vitaminocalcique est indispensable à tout âge. Le traitement de la douleur, très fréquente, ne doit pas non plus être négligé.

OBJECTIVE:To determine the incidence of renal AA amyloidosis and its association with rheumatoid arthritis (RA) in a cohort of all renal biopsies at one referral hospital and to measure the effect of a monthly pulse of cyclophosphamide on renal function and survival in these RA patients.METHOD:All renal biopsies with proven AA amyloidosis from a single pathology unit linked to a major nephrology referral unit in a university hospital were selected retrospectively and RA patients were identified. We studied 6931 renal biopsies. The effect of treatment with and without pulse cyclophosphamide on renal function and survival was studied in these patients.RESULTS:From March 1977 to February 1999, the incidence of AA amyloidosis was 2.4 cases/yr. The incidence and prevalence of the association of AA amyloidosis with RA were 0.68 cases/yr and 0.22% (15/6931) respectively. RA patients treated with cyclophosphamide (n=6) had a lower rate of renal function loss (P=0.013) and a higher median survival (P=0.026) than untreated patients (n=9). During the follow-up period, two out of six treated patients (33%) and all nine untreated patients (100%) died.CONCLUSIONS:AA amyloidosis is a rare complication of RA and complicates the evaluation of treatment. This retrospective study suggests that treatment with cyclophosphamide is able to reduce the incidence of end-stage renal failure and to increase survival. Prospective studies are needed to clarify this issue.

We report a case of dermatomyositis associated with molecular evidence of parvovirus B19 DNA in two muscle biopsies collected 5 months apart. IgG- but not IgM-specific antibodies were detected in serum. None of four serum samples was positive for parvovirus B19 DNA. The two biopsies contained B19 VP1 sequences and the second one was also positive for NS1. This is the first report of viral parvovirus B19 DNA in muscle of a patient with dermatomyositis. Latent muscle infection may contribute to the clinical picture.

Two case-reports of metastatic bone disease in patients with bronchial carcinoid tumors illustrate the diagnostic challenges raised by these slowly-growing malignancies of which the primary frequently escapes early identification. The first patient had the typical picture of a primary with a single bone metastasis. Unusual features in the second patient were the large number of bone metastases, involvement of distal skeletal sites, and elevation of serotonin and 5-hydroxyindoleacetic acid levels.