Functional neurological signs in hypermobile Ehlers-Danlos syndrome and hypermobile spectrum disorders with suspected neuropathic pain.

BACKGROUND: The hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are connective tissue disorders characterized by generalized joint hypermobility, associated with chronic pain and several symptoms, such as fatigue, dysautonomia, as well as psychiatric co-morbidities. Clinical observations of unusual manifestations during systematic sensory testing raised the question of a possible co-existence with a functional neurological disorder (FND). Hence, this study aimed to assess the presence of positive functional neurological signs (FNS) in a cohort of patients with hEDS/HSD. METHODS: The clinical data of hEDS/HSD patients (N = 24) were retrospectively analyzed and compared to a prospectively recruited age-/sex-matched healthy control group (N = 22). Four motor- and three sensory-positive FNS were assessed. RESULTS: Twenty-two patients (92%) presented at least one motor or sensory FNS. Five patients (21%) presented only a single FNS, 14 presented between 2 and 4 FNS (58%), and 3 patients presented 5 or more FNS (12%). None of the healthy controls presented motor FNS, and only two presented a sensory FNS. CONCLUSIONS: The presence of FNS in hEDS/HSD deserves better clinical detection and formal diagnosis of FND to offer more adequate care in co-morbid situations. In fact, FND can severely interfere with rehabilitation efforts in hEDS/HSD, and FND-targeted physical therapy should perhaps be combined with EDS/HSD-specific approaches.

Maintenance of bone resorption markers in the low premenopausal range during the year following denosumab discontinuation is associated to bone density preservation. The ReoLaus study.

PURPOSE: Denosumab discontinuation (DD) is associated with serum C-terminal X-linked telopeptides (sCTX) increase, bone mineral density (BMD) loss and vertebral fractures (VFs) risk increase. We compared clinical characteristics of women losing or not lumbar spine (LS) BMD one-year after DD, and their sCTX values at different time-points. METHODS: We included women from the ReoLaus cohort having received ≥2 denosumab 60 mg injections, with three BMD measurements on the same device (before (DXA1), at the end of denosumab treatment (DXA2), and one-year after (DXA3)) and sCTX measured at different time-points. Losers (LS DXA3-DXA2 > 2.8 %) and stable groups were compared. RESULTS: 63 postmenopausal women were included (mean age 64.2 ± 9.1 years, 7.9 ± 2.7 denosumab injections). 19 months after last denosumab injection, 65 % had lost LS BMD. Losers were younger, had lower BMD and higher sCTX before denosumab, received more injections and gained more BMD under denosumab, and had higher sCTX after DD. Same proportion of patients received bisphosphonates in both groups, but 11 (all in losers group) received ≥1 zoledronate infusion. Three women developed VFs in the losers group (none in the stable). Mean sCTX at 10 and 19 months were 590 ± 372 versus 221 ± 101, and 598 ± 324 versus 293 ± 157 ng/l, respectively (premenopausal range < 573 ng/l, p < 0.01 for both). LS BMD loss and sCTX levels measured at 10 and 19 months were correlated (r2 = 0.29, p = 0.01, and r2 = 0.16, p < 0.005). CONCLUSION: Maintenance of BMD gained with denosumab is associated with sCTX in the low premenopausal range after DD. Whether this could be achieved by regular sCTX monitoring and adjustment of bisphosphonates doses or frequency administration needs to be confirmed by further studies.

A novel approach for fibrous dysplasia assessment using combined planar and quantitative SPECT/CT analysis of Tc-99m-diphosphonate bone scan in correlation with biological bone turnover markers of disease activity.

Purpose: To investigate the emerging role of Tc-99m-labeled diphosphonate (Tc-99m-DPD) uptake quantification by SPECT/CT in fibrous dysplasia (FD) bone lesions and its correlation with biological bone turnover markers (BTMs) of disease activity. Materials and methods: Seven patients (49 ± 16 years) with a confirmed diagnosis of FD were included in this retrospective study. Bone scans with Tc-99m-DPD and quantitative SPECT/CT (xSPECT/CT) were performed. SUVmax (maximum standard unit value) and SUVmean (mean standard unit value) were measured in all FD bone lesions. The skeletal burden score (SBS) was assessed on planar scintigraphy and multiplied by mean SUV max and SUVmean to generate two new parameters, SBS_SUVmax and SBS_SUVmean, respectively. Planar and xSPECT/CT quantitative measures were correlated with biological BTMs of disease activity, including fibroblast growth factor 23 (FGF-23), alkaline phosphatase (ALP), procollagen 1 intact N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX), as well as scoliosis angle measured on radiographs. Statistical significance was evaluated with Spearman's correlations. Results: A total of 76 FD bone lesions were analyzed, showing an average SUVmax and SUVmean (g/mL) of 13 ± 7.3 and 8 ± 4.5, respectively. SBS, SBS_SUVmax and SBS_SUVmean values were 30.8 ± 25.6, 358 ± 267 and 220.1 ± 164.5, respectively. Mean measured values of FGF-23 (pg/mL), ALP (U/L), P1NP (µg/L) and CTX (pg/mL) were 98.4 (22-175), 283.5 (46-735), 283.1 (31-1,161) and 494 (360-609), respectively. Mean scoliosis angle was 15.7 (7-22) degrees. We found a very strong positive correlation between planar-derived SBS and CTX (r = 0.96, p = 0.010), but no significant correlation between SUVmax or SUVmean and biological BTMs. SBS_SUVmax showed a strong to very strong positive correlation with CTX (ρ = 0.99, p = 0.002), FGF-23 (ρ = 0.91, p = 0.010), ALP (ρ = 0.82, p = 0.020), and P1NP (ρ = 0.78, p = 0.039), respectively. Conclusion: This study showed that biological BTMs are significantly correlated with diphosphonate uptake on bone scan, quantified by a new parameter combining information from both planar and quantitative SPECT/CT. Further analysis of bone scan quantitative SPECT/CT data in a larger patient population might help better characterize the skeletal disease burden in FD, and guide treatment and follow-up.

Are patients with hypermobile Ehlers-Danlos syndrome or hypermobility spectrum disorder so different?

Diagnosing hypermobile Ehlers-Danlos syndrome (hEDS) remains challenging, despite new 2017 criteria. Patients not fulfilling these criteria are considered to have hypermobile spectrum disorder (HSD). Our first aim was to evaluate whether patients hEDS were more severely affected and had higher prevalence of extra-articular manifestations than HSD. Second aim was to compare their outcome after coordinated physical therapy. Patients fulfilling hEDS/HSD criteria were included in this real-life prospective cohort (November 2017/April 2019). They completed a 16-item Clinical Severity Score (CSS-16). We recorded bone involvement, neuropathic pain (DN4) and symptoms of mast cell disorders (MCAS) as extra-articular manifestations. After a standardized initial evaluation (T0), all patients were offered the same coordinated physical therapy, were followed-up at 6 months (T1) and at least 1 year later (T2), and were asked whether or not their condition had subjectively improved at T2. We included 97 patients (61 hEDS, 36 HSD). Median age was 40 (range 18-73); 92.7% were females. Three items from CSS-16 (pain, motricity problems, and bleeding) were significantly more severe with hEDS than HSD. Bone fragility, neuropathic pain and MCAS were equally prevalent. At T2 (20 months [range 18-26]) 54% of patients reported improvement (no difference between groups). On multivariable analysis, only family history of hypermobility predicted (favorable) outcome (p = 0.01). hEDS and HDS patients showed similar disease severity score except for pain, motricity problems and bleeding, and similar spectrum of extra-articular manifestations. Long-term improvement was observed in > 50% of patients in both groups. These results add weight to a clinical pragmatic proposition to consider hEDS/HSD as a single entity that requires the same treatments.

Diurnal Salivary Cortisol in Sarcopenic Postmenopausal Women: The OsteoLaus Cohort.

Sarcopenia, similar to hypercortisolism, is characterized by loss of muscle mass and strength. Cortisol circadian rhythm changes with aging (blunted late-day nadir values) were suggested to contribute to this decline. We aimed to explore the relationship between diurnal salivary cortisol values and sarcopenia diagnosis and its components in postmenopausal women. This is a cross-sectional study within the OsteoLaus population-based cohort in Lausanne (Switzerland). Participants had a body composition assessment by dual X-ray absorptiometry (DXA), a grip strength (GS) measure, and salivary cortisol measures (at awakening, 30 min thereafter, 11 AM (sc-11AM) and 8 PM (sc-8PM)). Associations between salivary cortisol and sarcopenia diagnosed by six different criteria (based on appendicular lean mass (ALM) assessed by DXA, and muscle strength by GS), and its components, were analyzed. 471 women aged > 50 years (63.0 ± 7.5) were included. Various definitions identified different participants as sarcopenic, who consistently presented higher salivary cortisol at 11 AM and/or 8 PM. There were no associations between salivary cortisol levels and ALM measures, either absolute or after correction to height squared (ALM index) or body mass index. GS was inversely correlated to sc-11AM (r = - 0.153, p < 0.001) and sc-8PM (r = - 0.118, p = 0.002). Each 10 nmol/l increase of sc-11AM, respectively sc-8PM, was associated with a GS decrease of 1.758 (SE 0.472) kg, respectively 2.929 (SE 1.115) kg. In postmenopausal women, sarcopenia is associated with higher salivary cortisol levels at 11 AM and 8 PM. An increase of daily free cortisol levels in the physiological range could participate to sarcopenia development by decreasing muscle function in postmenopausal women.

Comparison of paediatric and adult classification criteria in juvenile idiopathic arthritis during the transition from paediatric to adult care.

OBJECTIVES: To determine the characteristics of juvenile idiopathic arthritis (JIA) patients seen during the transition period in order to compare paediatric classification criteria with those for adults. METHODS: Patients with JIA according to the ILAR classification and who had a consultation at transition between 2010 and 2017 were included in a retrospective bi-centre (Lyon, Lausanne) study. JIA classification criteria were compared to ACR/EULAR 2010 criteria for rheumatoid arthritis (RA), Yamaguchi criteria for adult-onset Still's disease (AOSD), ASAS criteria for spondyloarthritis and CASPAR criteria for psoriatic arthritis. RESULTS: One hundred and thirty patients were included: 13.9% with systemic JIA, 22.3% with polyarticular JIA, 22.3% with oligoarticular JIA, 34.6% with enthesitis-related arthritis (ERA) and 6.9% with psoriatic arthritis; 13.1% had suffered from uveitis; 14.5% of patients had erosions or carpitis, mainly those with psoriatic arthritis, polyarticular or systemic JIA; 37.5% of patients with ERA displayed radiological sacroiliitis. When comparing paediatric JIA criteria with adult classifications, we found that: 66.6% of patients with systemic JIA fulfilled the criteria for AOSD, 87.5% of rheumatoid factor-positive polyarticular JIA and 9.5% of rheumatoid factor-negative polyarticular JIA met the criteria for RA, and 34.5% of oligoarticular JIA fulfilled the criteria for spondyloarthritis. Finally, 77.7% of patients with ERA met the criteria for spondyloarthritis, and 100% of patients with psoriatic arthritis JIA met the criteria for psoriatic arthritis. CONCLUSION: Oligoarticular JIA and rheumatoid factor-negative polyarticular JIA seem to be paediatric entities, whereas the other types of JIA tended to meet the respective adult classification criteria.

Osteogenesis imperfecta: towards an individualised interdisciplinary care strategy to improve physical activity and quality of life.

BACKGROUND: This report describes a new strategy for the care of patients with osteogenesis imperfecta, based on an interdisciplinary team working. Thereby, we aim at fulfilling three main goals: offering thorough coordinated management for all, and improving physical activity and quality of life of the patients. AIM: With rare diseases such as osteogenesis imperfecta (OI), patients and their family often suffer from inadequate recognition of their disease, poor care coordination and incomplete information. A coordinated interdisciplinary approach is one possible solution for providing both comprehensive and cost-effective care, with benefits for patient satisfaction. Poor physical activity and impaired quality of life represent a considerable burden for these patients. To better address these issues, in 2012 we created an interdisciplinary team for the management of OI patients in our University Hospital Centre (CHUV, Lausanne University Hospital,). In this article we describe the implementation of this interdisciplinary care strategy for patients suffering from OI, and its impact on their physical activity and quality of life. METHODS: All patients from the French part of Switzerland were invited to join us. We proposed two complementary evaluations: the initial interdisciplinary evaluation and a yearly follow-up during a special day – the “OI day”. This day features specialised medical appointments adapted to each patient’s needs, as well as lectures and/or workshops dedicated to patients’ and families’ education. Our first aim was to propose for each patient the same management, from diagnosis to the bone health evaluation and physical therapy advice. Our second aim was to evaluate the evolution of physical activity, quality of life (measured by EQ-5D, SF-36 and a dedicated questionnaire) and satisfaction of patients and their families. Here we report both the initial and the long-term results. RESULTS: Since 2012, 50 patients from the French part of Switzerland received the personalised medical evaluation. All of the patients included in this study had the same initial evaluation and at least one participation in an OI Day. All patients had an adaptation of their bone acting drugs. Over a 7-year period, 62% of inactive patients started some physical activity, and 44% of patients who were not involved in any athletic activity started participating in sports. The mean EQ-5D increased from 0.73 to 0.75 (p = 0.59). The mean physical SF36 (musculoskeletal function) score was 59.09 ± 22.72 and improved to 65.79 ± 21.51 (p = 0.08), whereas it was 68.06 ± 20.05 for the mental SF36 without alteration during follow-up. The OI day was revealed to be useful, it contributed to improvement in continuity of care and helped families to better understand the OI patients’ health. CONCLUSIONS: Our interdisciplinary approach aimed at offering the same thorough management for all patients from the French part of Switzerland, and at improving both the physical activity and the satisfaction of the patients and their family. This report is a basis for future work focusing on the effect of bone fragility and the impact of OI on patients’ social relations.

"Inflammaging" and bone in the OsteoLaus cohort.

BACKGROUND: "Inflammaging" is a coined term that combines the processes of inflammation (within the normal range) and aging, since chronic, low-grade, systemic inflammation emerges with increasing age. Unlike high-level inflammation, with which deleterious effects on bone no longer need to be demonstrated, it is unclear whether inflammaging exerts deleterious effects on bone too. METHOD: We assessed associations between inflammaging - measured via cytokine levels (high-sensitivity C-reactive protein (hs-CRP); interleukin-1ß (IL-1ß); interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)) - and bone parameters (prevalent and incident fractures, bone mineral density (BMD) and trabecular bone score (TBS)) in 1390 postmenopausal women from the OsteoLaus study. RESULTS: Mean (±SD) age was 64.5 ± 7.6 and mean bone mass index (BMI) 25.9 ± 4.5 kg/m2. Median hs-CRP, IL-1ß, IL-6 and TNF-α were 1.4 pg/ml, 0.57 pg/ml, 2.36 pg/ml and 4.82 pg/ml, respectively. In total, 10.50% of the participants had a prevalent, low-impact fracture; and, after 5-years of follow up, 5.91% had an incident, low-impact fracture. Mean T-score BMD was - 1.09 ± 1.53 for the spine, - 1.08 ± 1.02 for the femoral neck, and - 0.72 ± 0.96 for the total hip. Mean spine TBS was 1.320 ± 0.10. We found a positive association between hs-CRP and BMD at all sites, and between hs-CRP and the TBS, but none of these associations were significant after adjustment. We found no association between prevalent or incident fractures and hs-CRP. No association was found between IL-1ß, IL6 and TNF-α and BMD, TBS or fractures. CONCLUSION: Our results suggest that bone imaging and structure parameters are not associated with the low-grade cytokine levels (within the normal range) observed with inflammaging.

[Vertebroplasty: the new CHUV consensus]. / Fracture vertébrale ostéoporotique aiguë et douloureuse - Proposition d'un algorithme décisionnel pour la cimentoplastie au CHUV.

Should we continue to treat patients suffering from an acute osteoporotic vertebral fracture with vertebroplasty ? What is the potential benefit ? What are its indications ? What are its risks ? Which way to perform it ? How to manage the osteoporosis evaluation and therapy ? In 2009 we published the «â€…CHUV consensus ¼ on the management of vertebral osteoporotic fractures by vertebroplasty. We here propose an update including recent knowledge on the management of vertebral fractures by bone insufficiency by percutaneous cementoplasty.

Doit-on continuer à traiter les patients souffrant d'une fracture vertébrale aiguë ostéoporotique par cimentoplastie ? Quel est le bénéfice potentiel ? Quelles sont ses indications ? Quels sont ses risques ? À qui les adresser ? Quand faire le bilan et le traitement de la maladie ostéoporotique ? En 2009, nous avions publié le consensus du CHUV de prise en charge par vertébroplastie des fractures vertébrales ostéoporotiques. Nous proposons une mise à jour incluant les connaissances récentes sur la prise en charge des fractures vertébrales par insuffisance osseuse par technique de cimentoplastie percutanée.

OsteoLaus: raisons d'être et premiers résultats.

OsteoLaus: Right to Exist and First Results Abstract. The OsteoLaus cohort included 1475 women aged 50 to 80 years between 2010 and 2012, and since followed every 2.5 years. The main goal is to better define osteoporosis and the prediction of fracture risk. Using the multiple data available in CoLaus/PsycoLaus, many analyses are being conducted to better understand the relationship between bone health and chronic disease.

Résumé. La cohorte OsteoLaus a inclus 1475 femmes de 50 à 80 ans entre 2010 et 2012, et depuis suivies tous les 2,5 ans. Le but principal est de mieux définir l'ostéoporose et la prédiction du risque de fracture. Grâce aux multiples données à disposition dans CoLaus/PsycoLaus, de nombreuses analyses sont faites pour mieux comprendre le lien entre santé osseuse et maladies chroniques.

Sixty spontaneous vertebral fractures after denosumab discontinuation in 15 women with early-stage breast cancer under aromatase inhibitors.

PURPOSE: At denosumab discontinuation, bone turnover markers increase and the gained BMD is lost. In postmenopausal osteoporosis, there is an increased risk of spontaneous vertebral fractures (VFs) of about 1 to 10%, rarely described in women under denosumab for aromatase inhibitors (AI)-treated breast cancer. We aim to describe the characteristics of 15 patients under denosumab given for AI-treated early-stage breast cancer that presented VFs at its discontinuation. METHODS: Single-center retrospective case series of 15 patients. We report clinical data, dual X-ray absorptiometry values at denosumab initiation and discontinuation, and serum B-crosslaps dosage at the time of VF occurrence (before denosumab resumption). RESULTS: Fifteen women (66.4 ± 7.1 years at denosumab discontinuation) that received AI for 5.0 ± 0.6 years, denosumab 60 mg for 8.2 ± 2.0 doses, and developed 60 VFs at denosumab discontinuation, were followed for 24.4 ± 9.5 months. Patients suffered from 1 to 11 (mean 4.0 ± 1.9) clinical VFs within 7 to 16 months after last denosumab injection. VFs developed earlier in patients with longer denosumab treatment (R2 = 0.29, p = 0.04) and in patients without osteoporosis before denosumab (9.4 ± 2.0 vs. 13.0 ± 2.0 months; p = 0.005). Serum B-crosslaps at the time of VFs tended to be higher in patients with earlier VFs (R2 = 0.47; p = 0.06) or with longer denosumab treatment (R2 = 0.48; p = 0.06). Denosumab was resumed in all patients, then switched for a bisphosphonate in eight. No new VFs occurred during follow-up. CONCLUSIONS: Despite an apparently low fracture risk, women under denosumab for AI-treated early-stage breast cancer develop spontaneous VFs at denosumab discontinuation. This risk increases with treatment duration and may be prevented by a potent bisphosphonate.

Synovitis in rheumatoid arthritis detected by grey scale ultrasound predicts the development of erosions over the next three years.

OBJECTIVES: To evaluate grey scale US (GSUS) and power Doppler US synovitis (PDUS), separately or in combination (CombUS), to predict joint damage progression in RA. METHODS: In this cohort study nested in the Swiss RA register, all patients with sequential hand radiographs at their first US assessment were included. We analysed the summations of semi-quantitative GSUS, PDUS and CombUS assessments of both wrists and 16 finger joints (maximum 54 points) at their upper limit of normal, their 50th, 75th or 87.5th percentiles for the progression of joint damage (ΔXray). We adjusted for clinical disease activity measures at baseline, the use of biological DMARDs and other confounders. RESULTS: After a median of 35 months, 69 of 250 patients with CombUS (28%), 73 of 259 patients with PDUS (28%) and 75 of 287 patients with available GSUS data (26%) demonstrated joint damage progression. PDUS beyond upper limit of normal (1/54), GSUS and CombUS each at their 50th (9/54 and 10/54) and their 75th percentiles (14/54 and 15/54) were significantly associated with ΔXray in crude and adjusted models. In subgroup analyses, GSUS beyond 14/54 and CombUS higher than 15/54 remained significantly associated with ΔXray in patients on biological DMARDs, while clinical disease activity measures had no significant prognostic power in this subgroup. CONCLUSION: Higher levels of GSUS and CombUS are associated with the development of erosions. GSUS appears to be an essential component of synovitis assessment and an independent predictor of joint damage progression in patients on biological DMARDs.

Clinical Performance of the Updated Trabecular Bone Score (TBS) Algorithm, Which Accounts for the Soft Tissue Thickness: The OsteoLaus Study.

Regional soft tissue may have a noise effect on trabecular bone score (TBS) and eventually alter its estimate. The current TBS software (TBS iNsight®) is based on an algorithm accounting for body mass index (BMI) (TBSv3.03 ). We aimed to explore the updated TBS algorithm that accounts for soft tissue thickness (TBSv4.0 ). This study was embedded in the OsteoLaus cohort of women in Lausanne, Switzerland. Hip and lumbar spine (LS) dual-energy X-ray absorptiometry (DXA) scans were performed using Discovery A System (Hologic). The incident major osteoporotic fractures (MOFs) were assessed from vertebral fracture assessments using Genant's method (vertebral MOF) or questionnaires (nonvertebral MOF). We assessed the correlations of bone mineral density (BMD) or TBS with body composition parameters; MOF prediction ability of both versions of TBS; and the differences between Fracture Risk Assessment Tool (FRAX) adjusted for TBSv3.03 or TBSv4.0 . In total, 1362 women with mean ± SD age 64.4 ± 7.5 years and mean ± SD BMI 25.9 ± 4.5 kg/m2 were followed for 4.4 years and 132 experienced an MOF. All the anthropometric measurements of our interest were positively correlated with LS, femoral neck, or hip BMD and TBSv4.0 ; whereas with TBSv3.03 their correlations were negative. In the models adjusted for age, soft tissue thickness, osteoporotic treatment, and LS-BMD, for each SD decline in TBSv3.03 , there was a 43% (OR 1.43; 95% CI, 1.12 to 1.83) increase in the odds of having MOF; whereas for each SD decline in TBSv4.0 , there was a 54% (OR 1.54; 95% CI, 1.18 to 2.00) increase in the odds of having an MOF. Both FRAXs were very strongly correlated and the mild differences were present in the already high-risk women for MOF. This study shows that TBSv4.0 overcomes the debatable residual negative correlation of the current TBS with body size and composition parameters, postulating itself as free from the previously acknowledged technical limitation of TBS. © 2019 American Society for Bone and Mineral Research.