Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies.

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

European regulatory perspectives for innovative therapies.

The current regulatory requirements offer accelerated assessment of innovative therapies in Europe. Future perspectives include the need for increased interaction between stakeholders in pharmaceutical development. Development of new, high quality, effective and safe medicines in Europe is the common goal of academia, pharmaceutical industry and regulatory authorities. To achieve this, it is important that regulatory requirements do not hinder innovation and vice versa, innovation cannot be allowed to proceed without concerns for public health. Interaction between stakeholders in pharmaceutical development is of the utmost importance. A dialogue has begun and in the future it will be the responsibility of all stakeholders to ensure continuous exchanges in an environment that is characterised by new scientific advances and global development programmes.

An open, randomized, controlled study of transdermal hormone replacement therapy on the rate of bone loss in primary biliary cirrhosis.

OBJECTIVES: The prevalence of osteoporosis amongst patients with primary biliary cirrhosis (PBC) is high and may be a serious clinical problem. Hormone replacement therapy (HRT) is effective in preventing bone loss but has not been evaluated in randomized trials in PBC. The primary aim was to study the effect of transdermal HRT in combination with daily vitamin D and calcium supplementation on bone loss compared with vitamin D and calcium supplementation only in postmenopausal women with PBC. The secondary aim was to study the safety of transdermal HRT. SUBJECTS/INTERVENTIONS: Eighteen females with PBC were randomized to receive 2 years therapy with either (i) transdermal oestradiol 50 microg 24 h(-1) two times per week + medroxyprogesterone 2.5 mg day(-1) + alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1) or (ii) alfacalcidol 0.25 microg day(-1) and calcium 1 g day(-1). Dual-energy X-ray absorptiometry for measurement of bone mineral density (BMD) and sampling of blood and serum for measurements of biochemical markers of liver function was performed before, during and at the end of treatment. RESULTS: BMD increased significantly at the lumbar spine (P < 0.05) and the femoral neck (P < 0.05) in the HRT group whereas no significant change was found in the control group. One oestrogen-treated patient was excluded after 1 year because of deteriorating, but reversible, aminotransferases. Dropout frequency because of nonliver-related causes was higher in the HRT group. Otherwise, no difference with respect to adverse liver reactions was found between the groups. CONCLUSION: Transdermal HRT increases BMD in PBC patients with few severe side effects related to the liver.

Longitudinal bone loss in postmenopausal women with primary biliary cirrhosis and well-preserved liver function.

OBJECTIVES/DESIGN: Increased rate of bone loss has been reported in women with primary biliary cirrhosis (PBC) and varying degree of liver dysfunction. Whether bone loss is increased in patients without liver dysfunction is unclear. The aim of this study was to estimate retrospectively the rate of bone loss in postmenopausal women with PBC and well-preserved liver function. SUBJECTS/INTERVENTIONS: Forty-three women with PBC, and classified as Child-Pugh class A, were included. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at the lumbar spine and the femoral neck. RESULTS: Median time between measurements of BMD was 26 months (range, 12-48 months). Twenty women were not receiving any bone protective treatment, i.e. hormone replacement therapy (HRT), bisphosphonates or vitamin D/calcium supplementation, whilst 23 women received such treatment. Mean annual bone loss in the former group was 0.38 +/- 2.56% and 0.42 +/- 2.29% at the lumbar spine and the femoral neck, respectively. Women receiving treatment, however, increased their BMD by 1.92 +/- 3.76% and 0.15 +/- 2.75% at the lumbar spine and the femoral neck, respectively. At the lumbar spine the difference with regard to changes in BMD between untreated and treated women was statistically significant (P = 0.02). Women who received HRT (n = 11) increased their BMD at the lumbar spine by 2.95 +/- 3.91%, P = 0.03 when compared with untreated women. CONCLUSION: Bone loss in postmenopausal women with PBC and well-preserved liver function is not increased above normal. Treatment with bone protective treatment, mainly HRT, improves BMD at the lumbar spine.

Circulating levels of insulin-like growth factors and their binding proteins in patients with chronic liver disease: lack of correlation with bone mineral density.

BACKGROUND/AIMS: Insulin-like growth factor-I (IGF-I) levels are low in patients with chronic liver disease (CLD) and have been found to correlate with measurements of bone mineral density (BMD) in men with viral cirrhosis. The aim of this study was to investigate the relationship between circulating IGF-I levels and BMD in patients with CLD of other causes. METHODS: Fifty-eight patients with CLD were included. Age- and sex-matched normal individuals served as controls. Serum levels of IGF-I and IGF-II and their binding proteins (IGFBP-1-3) were measured by radioimmunoassay. BMD was measured by dual energy X-ray absorptiometry. RESULTS: IGF-I levels were 57+/-33 and 136+/-48 ng/ml; p<0.0001 in patients and controls, respectively. IGF-II and IGFBP-3 levels were lower (p<0.0001) and IGFBP-1 and IGFBP-2 levels were higher in patients compared with controls (p<0.0005 and p<0.0001, respectively). All growth factors, except for IGFBP-2, correlated with parameters of liver function. In a multiple regression analysis, adjusting for age, no correlation was found between IGF-I, IGF-II, IGFBP-1-3 and BMD in either patients or controls. CONCLUSION: Patients with CLD have low levels of IGF-I, IGF-II and IGFBP-3 that correlate with liver function. No relationship was found between low levels of growth factors and BMD.

Inverse relationship between circulating levels of leptin and bone mineral density in chronic liver disease.

BACKGROUND AND AIM: The pathophysiology of osteoporosis complicating chronic liver disease is unknown. Recent animal studies have found leptin to be a potent inhibitor of bone formation. The aim of this study was to investigate the relationship between serum leptin levels and bone mineral density in patients with chronic liver disease. METHODS: Fifty-eight patients, 39 females and 19 males, and age- and gender-matched controls were included. Bone mineral density was measured by using dual energy X-ray absorptiometry. Serum leptin was measured by using a radioimmunoassay. RESULTS: The mean serum leptin concentration was 10.4 +/- 11.3 and 15.2 +/- 17.9 ng/mL; P=0.11, in the patients and controls, respectively. Leptin correlated positively with body mass index in patients (r=0.40; P=0.003) and in controls (r=0.55; P < 0.0001). In patients classified as Child-Pugh grade B and C, serum leptin correlated negatively with bone mineral density in females at both the lumbar spine and the femoral neck (r=-0.78; P=0.04 and r=-0.86; P=0.03, respectively). In male patients, the correlation was only significant at the lumbar spine (r=-0.99; P=0.002 and r=-0.86; P=0.06, at the lumbar spine and femoral neck, respectively). No correlation was found between serum leptin and bone mineral density in the controls. CONCLUSION: An inverse relationship between serum leptin and bone mineral density was found in patients with advanced chronic liver disease. The reasons for these findings are uncertain, but a pathophysiological role of circulating leptin in osteoporosis in chronic liver disease is possible.

Low body mass index and use of corticosteroids, but not cholestasis, are risk factors for osteoporosis in patients with chronic liver disease.

BACKGROUND/AIMS: Metabolic bone disease is known to complicate chronic liver disease. In a cross-sectional, controlled study we have studied the prevalence of osteoporosis in patients with various types of chronic liver disease. We also identified risk factors predisposing to osteoporosis in this patient group. METHODS: Seventy-two hospitalised patients, 46 females and 26 males, were included. Age- and sex-matched individuals from the background population served as controls. Bone mineral density was measured by dual energy X-ray absorptiometry at the lumbar spine and femoral neck. RESULTS: Bone mineral density was significantly lower in patients with chronic liver disease than in controls at the lumbar spine (Z-score: -0.35 SD+/-1.36 vs. 0.26 SD+/-1.19, p<0.01) but not at the femoral neck (Z-score: -0.18 SD+/-1.48 vs. 0.17 SD+/-1.08, NS). Patients with cholestatic chronic liver disease did not have lower bone mineral density compared with patients with non-cholestatic chronic liver disease (Z-score: -0.35 SD+/-1.30 vs. -0.34 SD+/-1.45). Osteoporosis was found in 30% of the patients and 15% of the controls, respectively. In a multivariate regression analysis on risk factors in the patient group, the following factors were associated with osteoporosis: use of corticosteroids (odds ratio=18.9; p<0.01), low body mass index (odds ratio=14.1; p=0.001), high age and female sex. CONCLUSION: Patients with chronic liver disease are at risk of developing osteoporosis. Risk factors for osteoporosis in chronic liver disease are low body mass index and corticosteroid therapy, in addition to high age and female sex. Cholestatic liver disease per se is not associated with an increased risk for osteoporosis.

Evaluation of in vivo immune complex formation and complement activation in patients receiving intravenous streptokinase.

The usefulness of several different methods for detecting immune complex formation and complement activation in the circulation were applied to samples from patients receiving intravenous Streptokinase therapy for myocardial infarction. Streptokinase is a foreign antigen and can cause immune reactions. We collected samples from 13 patients, before Streptokinase administration (baseline), at the end of infusion (1 h), 12 h later and on day 7. We measured IgG containing immune complexes (IgG-IC), free C3d and antibodies to Streptokinase by ELISA, and CR1, C3d and C4d on erythrocytes by flow cytometric assay. Antibodies to Streptokinase are common, as all but two of the patients had measurable antibody levels. During Streptokinase treatment there was a drop in antibody levels, most prominent in those patients who had high baseline levels. At the same time increased levels of free C3d and erythrocyte-bound C3d were observed. After 12 h free C3d was usually back to baseline level, but C3d on erythrocytes was still raised. These data indicate the formation of Streptokinase immune complexes in patients with high Streptokinase antibody levels, and show that these complexes are cleared rapidly from the circulation, leaving more persistent signs of complement activation. We conclude that free C3d is a good indicator of ongoing complement activation, whereas C3d on erythrocytes indicates that complement activation has recently taken place.