Liana Euller-Ziegler

Oxytocin Controls Differentiation of Human Mesenchymal Stem Cells and Reverses Osteoporosis

Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose‐derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham‐operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.

Maintenance of infliximab treatment in ankylosing spondylitis: Results of a one‐year randomized controlled trial comparing systematic versus on‐demand treatment

OBJECTIVE Continuous treatment with the anti-tumor necrosis factor alpha (anti-TNFalpha) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested. METHODS Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58. RESULTS Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P<0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean+/-SD 5.8+/-2.2 versus 3.5+/-2; P<0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered. CONCLUSION These findings indicate that continuous treatment of AS with infliximab is more efficacious than on-demand treatment, and that the addition of MTX to infliximab provides no significant benefit.

Effect of discontinuing TNFα antagonist therapy in patients with remission of rheumatoid arthritis

OBJECTIVE The objective of this study was to determine the time to relapse after tumor necrosis factor alpha (TNFalpha) antagonist discontinuation in patients with remission of rheumatoid arthritis (RA). METHODS Among 304 patients taking TNFalpha antagonist therapy for RA, 21 achieved a remission and were taken off the TNFalpha antagonist. Remission was defined as DAS28<2.6 for at least 6 months without nonsteroidal inflammatory drugs or more than 5 mg of prednisone per day but with disease-modifying antirheumatic drug (DMARD) therapy if needed. The same TNFalpha antagonist was restarted in the event of a relapse (DAS28>3.2). RESULTS The 21 patients had a mean age of 61 years, a mean disease duration of 11.3 years, and a mean remission duration at TNFalpha antagonist discontinuation of 19.2 months. The TNFalpha antagonist was infliximab in 2 patients, adalimumab in 5, and etanercept in 14; and 14 patients were taking a concomitant DMARD. The number of patients still in remission after TNFalpha antagonist discontinuation was 9/20 after 6 months and 5/20 after 12 months. Mean time to relapse was 14.7 weeks. While off TNFalpha antagonist therapy, 3 of the 5 relapse-free patients after 12 months were on DMARD therapy, compared to 11 of the 15 patients who relapsed. Compared to the 15 patients who relapsed, the 5 relapse-free patients had a longer time on TNFalpha antagonist therapy (56 months vs. 35 months, P=0.012) and a longer time in remission on TNFalpha antagonist therapy (35 months vs.14.5 months, P=0.04). The 15 patients who relapsed consistently achieved a remission after resuming TNFalpha antagonist therapy; the remission occurred within 2 months in 13 patients. CONCLUSION TNFalpha antagonist discontinuation in patients in remission of RA was followed by a relapse within 12 months in 75% of cases. Relapsing patients responded well to resumption of the same TNFalpha antagonist.

Prevalence of symptomatic hip and knee osteoarthritis: a two-phase population-based survey1

OBJECTIVE Osteoarthritis (OA) epidemiologic data are scarce in Europe. To estimate the prevalence of symptomatic knee and hip OA in a multiregional sample in France. DESIGN A two-phase population-based survey was conducted in six regions in 2007-2009. On initial phone contact using random-digit dialing, subjects 40-75 years old were screened with a validated questionnaire. Subjects screened positive were invited for ascertainment: physical examination and hip and/or knee radiography (Kellgren-Lawrence grade≥2). Multiple imputation for data missing not-at-random was used to account for refusals. RESULTS Of 63,232 homes contacted, 27,632 were eligible, 9621 subjects screened positive, 3707 participated fully in the ascertainment phase, and 1010 had symptomatic OA: 317 hip, 756 knee. Hip OA prevalence according to age class ranged from 0.9% to 3.9% for men and 0.7-5.1% for women. Knee OA ranged from 2.1% to 10.1% for men and 1.6-14.9% for women. Both differed by geographical region. The hip and knee standardized prevalence was 1.9% and 4.7% for men and 2.5% and 6.6% for women, respectively. CONCLUSIONS This confirmed the feasibility of using a screening questionnaire for eliciting population-based estimates of OA. In France, it increases with age and is greater among women above the age of 50. The geographical disparity of hip and knee OA parallels the distribution of obesity. Study registration ID number 906297 at http://www.clinicaltrials.gov/.

Effect of Hyaluronic Acid in Symptomatic Hip Osteoarthritis : A Multicenter, Randomized, Placebo-Controlled Trial

OBJECTIVE To evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA). METHODS A multicenter, randomized, parallel-group, placebo-controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment. RESULTS Eighty-five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent-to-treat analysis (mean +/- SD decrease 7.8 +/- 24.9 mm with HA versus 9.1 +/- 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events. CONCLUSION Our findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.

Hip osteoarthritis: short-term efficacy and safety of viscosupplementation by hylan G-F 20. An open-label study in 22 patients

UNLABELLED We studied the short-term safety and efficacy of intraarticular hylan G-F 20 (Synvisc) in patients with symptomatic hip osteoarthritis. METHODS In this open-label prospective study, patients who had hip osteoarthritis with a visual analog pain scale score greaterthan 40/100 and a Lequesne index greater than 6 received one or two intra-articular injections of hylan G-F 20 under fluoroscopic guidance. The patients were evaluated once a month. A response was defined as a 50% decrease in the Lequesne score after 1 month as compared to baseline. RESULTS Thirty injections were performed in 22 patients with a mean age of 54 years. The response rate was 50% (11/22) after the first injection. Five of the 11 patients who failed to respond to the first injection received a second injection on day 30; two had a response, yielding a cumulative response rate of 13/22. In the six patients followed up for more than 6 months, the improvement was sustained. Short-term safety was satisfactory, with a self-limited exacerbation of pain during the first few days in three patients but no infections or other side effects.

Impact of a nurse-led programme on comorbidity management and impact of a patient self-assessment of disease activity on the management of rheumatoid arthritis: results of a prospective, multicentre, randomised, controlled trial (COMEDRA)

Objectives Rheumatoid arthritis (RA) patients are at an increased risk of developing comorbid conditions. A close monitoring of the disease targeting a status of low disease activity is associated with a better outcome. The aim of this trial was to evaluate the impact of a nurse-led programme on comorbidities and the impact of patient self-assessment of disease activity on the management of RA. Methods We enrolled 970 patients (mean age 58 years, 79% women) in a prospective, randomised, controlled, open-label, 6-month trial. In the comorbidity group (n=482), the nurse checked comorbidities and sent the programme results to the attending physicians. In the self-assessment group (n=488), the nurse taught the patient how to calculate his/her Disease Activity Score which had to be reported on a booklet to be shared with the treating rheumatologist. The number of measures taken for comorbidities and the percentage of patients recording a change (initiation, switch or increased dose) in disease-modifying antirheumatic drugs (DMARDs) in the 6 months follow-up period of the study defined the outcomes of the trial. Results The number of measures taken per patient was statistically higher in the comorbidity group: 4.54±2.08 versus 2.65±1.57 (p<0.001); incidence rate ratio: 1.78 (1.61–1.96) and DMARD therapy was changed more frequently in the self-assessment group: 17.2% versus 10.9% (OR=1.70 (1.17; 2.49), p=0.006). Conclusions This study demonstrates the short-term benefit of a nurse-led programme on RA comorbidity management and the impact of patient self-assessment of disease activity on RA treatment intensification. Trial registration number NCT #01315652.

Insufficiency fracture of the sacrum revealing a pregnancy associated osteoporosis. First case report

Osteoporosis of pregnancy, usually responsible for spinal or femoral fracture,1 is rare as is insufficiency fracture of the sacrum, usually occurring in the elderly.2Magnetic resonance imaging (MRI) permitted during pregnancy, led us to diagnose an insufficiency fracture of the sacrum revealing a pregnancy associated osteoporosis, never previously reported to the best of our knowledge. Rheumatologists need to be aware of this new cause of pelvic pain during pregnancy. A 29 year old pregnant (seventh month) woman presented with a spontaneous acute claudication in conjunction with a left hyperalgesic buttock pain. Her past medical history showed: low back pain, since the second month of her pregnancy, relieved by rest and paracetamol; smoking (10 packet years) stopped at the sixth month of pregnancy; one spontaneous miscarriage at six months responsible for …

Erdheim-Chester disease: typical radiological bone features for a rare xanthogranulomatosis

A 55 year old man was admitted to the rheumatology department owing to inflammatory back pain (occurring at 4 00 am, not aggravated by movement) without sciatica, increasingly severe over two years and associated with asthenia and weight loss (10 kg). No abnormalities were found on physical examination, except for tenderness on palpation of the spinous processes of L5 and S1. There was no significant past medical history. Laboratory tests showed a mild inflammatory picture: erythrocyte sedimentation rate 25 mm/1st h (normal 5–15), C reactive protein 12 mg/l (normal 0–10), fibrinogen 5.1 g/l (normal 2–4). Protein electrophoresis, red and white blood cell count, glucose, renal, and liver function tests were normal. Chemical bone markers (urinary pyridinoline, alkaline phosphatase, osteocalcin, parathormone, 25-hydroxyvitamin D, serum calcium and phosphorus, and urinary calcium and phosphorus) were normal. Standard lumbar spine and pelvic radiographs were normal. Technetium-99m bone scintigraphy showed no abnormal uptake in the spine or skull but disclosed an increased peripheral uptake. A skeletal survey showed multiple mixed bone lesions with sclerotic areas surrounding smaller lytic foci. These roughly bilateral, symmetrical lesions involved the metaphyses and diaphyses of some long bones but spared the epiphyses. Bones affected were the femora, tibiae, radii, wrist, and tarsal bones (fig 1). Figure 1 Skeletal bone radiographs showed bilateral and symmetrical cortical osteosclerosis of the …

The receptor activator of nuclear factor (NF)-κB ligand (RANKL) is a new chemotactic factor for human monocytes

Bone resorption is regulated by the immune system, where receptor activator of nuclear factor (NF)κB ligand (RANKL), a new member of the tumor‐necrosis factor family, may contribute to pathological conditions. Due to the role of RANKL in the maturation of monocyte‐derived osteoclasts, we hypothesized that RANKL could exert chemotactic properties toward monocytic cells. Our results demonstrate that RANKL induces the migration of MonoMac‐6 monocytic cells as well as human freshly isolated total peripheral blood mononuclear cells (PBMC) and CD14+ purified PBMC. RANKL induces the migration of MonoMac‐6 cells in a dose‐dependent manner and with an efficacy similar to MCP‐1. After an 8‐h incubation, the soluble form of RANKL (sRANKL) started to exhibit a chemoattractive effect on MonoMac‐6 cells, with an increased effect observed up to 24 h. RANKL elicits an additive chemotactic effect to MCP‐1. Furthermore, addition of the RANKL decoy receptor osteoprotegerin in the lower well or RANKL in the upper well abrogates the RANKL‐induced migration of MonoMac‐6 cells, hallmarking a true specific activity. RNase protection assay experiments indicate that exposure of MonoMac‐6 cells to RANKL had no significant effect on the expression of a variety of chemokines, known to attract monocytes. This study provides evidence that RANKL behaves as a chemotactic factor for monocytic cells, emphazing the cross‐talk between bone and immune systems.