Detection of hypophosphatasia in hospitalised adults in rheumatology and internal medicine departments: a multicentre study over 10 years.

INTRODUCTION: Hypophosphatasia (HPP) is a rare genetic disease caused by loss-of-function mutations in the ALPL gene encoding the tissue non-specific alkaline phosphatase (ALP). Mild HPP is usually misdiagnosed in adult age. While an elevated serum ALP value draws more attention than a low value, low serum ALP should be better recognised and may lead to HPP detection. METHODS: Patients were selected from the records of the biochemistry department of six University Hospitals in France. Patients were hospitalised in the departments of rheumatology and internal medicine between 2007 and 2017. RESULTS: 56 321 hospitalised patients had at least 2 serum ALP dosages and 664 of these patients had at least 2 low serum ALP≤35 UI/L. Among these 664 patients, 482 (72.6%) had fluctuating low values (mean age 62.9 years; 60% of women) and 182 patients (27.4%) had persistent low values below 35 IU/L (mean age 53.4 years; 67% of women). Among patients with persistent hypophosphatasaemia treated with bisphosphonates, 70.8% never had ALP measurement before treatment and 20.8% were treated despite an abnormal decrease of ALP. Genetic testing was performed in 18 patients and was positive in 11. Genetic diagnosis of HPP was at least 6.0% in persistent hypophosphatasaemia and at least 15.9% in patients with at least three symptoms suggestive of HPP. CONCLUSION: In this 10-year retrospective study, 0.32% of adult patients hospitalised in the rheumatology and internal medicine departments had persistently low serum ALP, and among them, 6% had genetically proven HPP. Reported hypophosphatasaemia represented only 3.6% of hospitalised patients.

Differences in bone microarchitecture between genetic and secondary iron-overload mouse models suggest a role for hepcidin deficiency in iron-related osteoporosis.

Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.

Ultrasound Classification of Finger Pulp Blood Flow in Patients With Systemic Sclerosis: A Pilot Study.

OBJECTIVE: To define a semiquantitative classification of finger pulp blood flow (FPBF) and to evaluate whether this classification could be used to assess FPBF in healthy controls and in systemic sclerosis (SSc) patients. METHODS: Thirty controls and 86 SSc patients were consecutively included. A classification of FPBF including 5 grades (from grade 0 [no signal] to 4 [signal detected on the entire finger pulp, including the subepidermal vascular network]) was evaluated. This classification was explored in basal conditions and after hand baths in hot and cold water in controls. Its relevance was also assessed at room temperature in SSc patients. RESULTS: In controls, power Doppler ultrasonography (PDUS) of FPBF was improved after hot challenge (P = 0.024), whereas cold challenge decreased FPBF (P = 0.001). FPBF correlated with the vasodilation status assessed by the resistivity index of radial arteries (Spearman's correlation coefficient = -0.50, P = 0.0049). Grade 0 was more frequent in SSc patients than in controls (22.1% versus 3.3%; P < 0.05). In SSc patients, grade 0 was associated with severity markers of the digital vasculopathy such as digital ulcers (DUs) (current or past) (P < 0.05) or ulnar artery occlusion (P < 0.05). On the other hand, DUs were less frequent in patients with grade 4 (P < 0.05). A pathologic threshold of <2 (grade 0 or 1) was significantly associated with DUs (odds ratio 6.67 [95% confidence interval 2.31-19.21], P < 0.0001). CONCLUSION: PDUS allowed a semiquantitative evaluation of FBPF in SSc patients and controls. Further studies are warranted to validate these results in independent SSc populations and to compare PDUS to existing tools assessing digital blood flow.

Should we really include systemic sclerosis specific antibodies in the classification criteria of Sjogren's disease?

We have read with great interest the results from Marketos et al. regarding the positivity of specific systemic sclerosis auto-antibodies in patients with sicca symptoms. Based on complementary data from the literature, we rather believe scleroderma-associated antibodies should be considered either as a yellow flag for an association between scleroderma and Sjogren, or a potential undiagnosed scleroderma, rather than an isolated Sjogren's disease.

Sicca syndrome in systemic sclerosis: a narrative review on a neglected issue.

SSc is an auto-immune disease characterized by life-threatening manifestations such as lung fibrosis or pulmonary arterial hypertension. Symptoms with a detrimental impact on quality of life are also reported and sicca syndrome (xerostomia, xeropthalmia) is present in up to 80% of patients with SSc. Sicca syndrome can occur in the absence of overlap with Sjögren's disease and recent studies highlight that fibrosis of minor and major salivary glands, directly linked to the pathogenesis of SSc, could be a major contributor of xerostomia in SSc. This narrative review provides an overview of the clinical presentation, diagnostic strategies, management and future perspectives on sicca syndrome in patients with SSc.

Rapid assembly of a polar network architecture drives efficient actomyosin contractility.

Actin network architecture and dynamics play a central role in cell contractility and tissue morphogenesis. RhoA-driven pulsed contractions are a generic mode of actomyosin contractility, but the mechanisms underlying how their specific architecture emerges and how this architecture supports the contractile function of the network remain unclear. Here we show that, during pulsed contractions, the actin network is assembled by two subpopulations of formins: a functionally inactive population (recruited) and formins actively participating in actin filament elongation (elongating). We then show that elongating formins assemble a polar actin network, with barbed ends pointing out of the pulse. Numerical simulations demonstrate that this geometry favors rapid network contraction. Our results show that formins convert a local RhoA activity gradient into a polar network architecture, causing efficient network contractility, underlying the key function of kinetic controls in the assembly and mechanics of cortical network architectures.

Drivers for primary producers' dynamics: New insights on annual benthos pelagos monitoring in anthropised freshwater marshes (Charente-Maritime, France).

Wetlands, especially marshes, support many services such as carbon catchment control or water purification led by primary producers such as phytoplankton and microphytobenthos (PB). The impact of the sedimentary compartment, as source and sink of essential nutrients for the water column, is often neglected in the study of their dynamics and water purification capacity of the systems. This work compared monthly (between February 2020 and April 2021) the benthic and pelagic primary producers' dynamics in two anthropised freshwater marshes (Marans and Genouillé), with the simultaneous follow-up of physico-chemical parameters of the water column and nutrient fluxes at the sediment-water (SWI) interface. It was suggested a strong contribution of phytoplankton (pumping) and the benthic compartment (denitrification) to the water purification of these two nitrates (NO3-)-rich marshes. Total phytoplankton production fluctuated between ∼5 (winter) and 1500 mg C m-3 d-1 (fall) at Marans and between 40 (winter) and ∼750 mg C m-3 d-1 (spring) at Genouillé. At Marans, soluble reactive phosphorus (SRP) benthic effluxes (-2.101 to -6.102 µmol m-2 d-1 in fall and summer, respectively) coincided with phytoplankton bloom periods. These effluxes were inhibited by NO3- penetration in the sediment (0 to 5.104 µmol m-2 d-1), by inhibiting iron respiration. At Genouillé, inhibition of SRP effluxes depended on denitrification rate and on P stocks in the sediment, where slight SRP effluxes (-101 µmol m-2 d-1) could have co-occurred with slight NO3- influxes (5.102 µmol m-2 d-1) in spring. The presence of PB (between 10-60 and 40-120 mg gsed-1 at Marans and Genouillé, respectively), suggested a strong contribution of the benthic compartment to the total primary production (benthic and pelagic through resuspension processes) in these environments. This work encourages to consider the benthos and the pelagos as a unicum to provide better sustainable management of such systems and limit eutrophication risks in coastal areas.

Patient-reported outcomes and their relation with iron parameters in HFE haemochromatosis during maintenance therapy: A prospective cohort study.

BACKGROUND & AIMS: The standard of care for haemochromatosis is regular phlebotomy in order to maintain low ferritin levels. Many patients report fatigue or joint pain despite serum ferritin within the therapeutic targets. We evaluated Patient-Reported Outcomes, and their relation with iron parameters, in C282Y homozygous patients undergoing maintenance phlebotomy. METHODS: Patients were prospectively enrolled in a French referral care centre. At each phlebotomy, patients completed a numeric fatigue scale, a joint pain questionnaire and SF-36 Mental Component Score (MCS) and Physical Component Score (PCS). Haemoglobin, iron, TS and ferritin were collected concomitantly. RESULTS: About 701 visits were performed in 259 patients. The median fatigue score was 3/10; 171 (66%) patients reported joint pain. Age and worsening of joint pain were associated with fatigue (p < .0001 for both). Female gender (p < .037), age (p < .003), and a decrease of TS (p = .050) were associated with joint pain. Main features associated with PCS <50 were worsening of joint pain and age (p < .001 for both) and TS <20% (p < .02). CONCLUSIONS: Fatigue was independent from iron parameters. The main factor impacting quality of life was joint pain, which was more severe in patients with low TS values. Then, a more precise monitoring of TS should be proposed during haemochromatosis maintenance therapy; while less stringent monitoring of serum ferritin levels could be tested.

Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload.

BACKGROUND: Iron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra-pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes. METHODS: The impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 µM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis. RESULTS: In vitro, iron exposure caused dose-dependent increases of iron storage protein ferritin (P < 0.01) and dose-dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra-physiological iron treatment (50 µM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 µM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF-κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle. CONCLUSIONS: Together, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.

Calcium pyrophosphate deposition (CPPD) in a liver transplant patient: are hypomagnesemia, tacrolimus or both guilty? A case-based literature review.

Calcium pyrophosphate deposition (CPPD) can be induced by a persistent hypomagnesemia. Tacrolimus is an immunosuppressive treatment especially used in organ transplant, potentially inducer of hypomagnesemia by renal loss. A 53-year-old man, liver transplant 10 months earlier, developed an acute peripheral oligoarthritis of wrist, hip and elbow with fever, associated with acute low back pain. Synovial fluid was sterile, and revealed calcium pyrophosphate crystals. Spinal imaging showed inflammatory changes. Magnesium blood level was low at 0.51 mmol/l, with high fractional excretion in favor of renal loss. Tacrolimus was changed for everolimus, proton pump inhibitor was stopped, and magnesium oral supplementation was started. After 8 months follow-up and slow prednisone tapering, he did not relapse pain. Persistent hypomagnesemia is a rare secondary cause of CPPD. In this entity, drug liability should be investigated such as tacrolimus in organ transplant patient.

Diagnostic Performances of Ultrasound Evaluation of Major Salivary Glands According to the 2019 Outcome Measures in Rheumatology Ultrasound Scoring System.

OBJECTIVE: To evaluate the diagnostic performance of ultrasound examination of the salivary glands (US-SG) according to the 2019 Outcome Measures in Rheumatology (OMERACT) US scoring system for Sjögren's syndrome (SS). METHODS: The present work was a retrospective study based on a multicentric cohort with SS/sicca syndrome. The American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2016 classification criteria for SS (a score of ≥4 without ocular staining score), the American-European Consensus Group (AECG) 2002 classification criteria, and clinician experts were considered as reference standards for diagnosis of SS. An OMERACT score of ≥2 according to 2 independent readers defined the diagnosis of SS based on US-SG assessment. Diagnostic performances and interobserver reproducibility of US-SG were assessed. RESULTS: Forty-two patients fulfilling the ACR/EULAR 2016 criteria for SS were compared to 30 control subjects with sicca syndrome. Twenty-five patients were diagnosed as having SS according to US-SG evaluation, and they were more frequently observed in the SS group (52.5%) than in the control group (10.0%) (P < 0.001). US-SG showed an area under the curve (AUC) of 0.751 (95% confidence interval [95% CI] 0.621, 0.882) for the diagnosis of SS (ACR/EULAR 2016 classification). The inclusion of US-SG in the ACR/EULAR 2016 classification improved sensitivity (91.5% versus 89.4%) with limited decrease of specificity (96.0% versus 100%) and with an AUC of 0.975 (95% CI 0.945, 1.00). Similar results were observed when US-SG was included in the AECG 2002 classification criteria. Interobserver reproducibility of a score of ≥2 according to the 2019 OMERACT US scoring system for SS diagnosis was good (κ = 0.73 [95% CI 0.64, 0.81]). Histologic lymphocyte infiltration of the minor salivary glands was associated with the OMERACT grading of US-SG. CONCLUSION: The present study confirms the good specificity of the 2019 OMERACT US classification measures of US-SG for the diagnosis of SS and its feasibility in daily practice.

Denosumab in the management of Aneurysmal bone cyst.

BACKGROUND: Aneurysmal bone cyst (ABC) is a benign, locally aggressive tumour that arises predominantly in long bones and spine. Following the encouraging results of denosumab use in Giant Cell Tumors (GCT) and the histological similarities between ABC and GCT, the interest on the role of denosumab in the therapeutic arsenal of the most advanced ABC is growing. The purpose of this literature review is to investigate the current state of knowledge about the use of denosumab in ABCs. METHODS: A literature research was conducted through PUBMED, COCHRANE and GOOGLE SCHOLAR using the keywords "aneurysmal bone cyst" AND "denosumab". Seventeen articles were included. RESULTS: A total of 43 cases were reported in the literature. There were 23 males, 20 females. The mean age was 15,9±8,1 year. Pain relief and neurological improvement were rapid and sustained. Radiological assessment showed ossification and/or volume reduction in 36/39 patients. Eight patients (18,6%) presented a recurrence after or during denosumab therapy of whom 7 were adults. Adverse events occurred in 11 patients, 5 of them were admitted to the intensive care unit due to hypercalcemia. CONCLUSION: Denosumab use in non-surgical ABCs has shown a positive impact in pain and neurological symptoms. The oncological outcome remains unclear with a recurrence rate of 18,6% during/after denosumab therapy, mostly in adults. However, regarding the potential clinical benefits, its use might be discussed in the most advanced cases. Further research and clinical trials are mandatory to precise its belonging in the therapeutic arsenal.

High-resolution dynamic mapping of the C. elegans intestinal brush border.

The intestinal brush border is made of an array of microvilli that increases the membrane surface area for nutrient processing, absorption and host defense. Studies on mammalian cultured epithelial cells have uncovered some of the molecular players and physical constraints required to establish this apical specialized membrane. However, the building and maintenance of a brush border in vivo has not yet been investigated in detail. Here, we combined super-resolution imaging, transmission electron microscopy and genome editing in the developing nematode Caenorhabditis elegans to build a high-resolution and dynamic localization map of known and new brush border markers. Notably, we show that microvilli components are dynamically enriched at the apical membrane during microvilli outgrowth and maturation, but become highly stable once microvilli are built. This new toolbox will be instrumental for understanding the molecular processes of microvilli growth and maintenance in vivo, as well as the effect of genetic perturbations, notably in the context of disorders affecting brush border integrity.

[Side effects of longterm oral corticosteroid therapy]. / Effets indésirables de la corticothérapie orale au long cours.

Side effects of long-term oral corticosteroid therapy. Systemic corticosteroid therapy has been used for over 70 years, and is still the cornerstone of the treatment of many conditions, in particular systemic, autoimmune or inflammatory diseases. Side effects of corticosteroids are numerous, and for most of them well known by prescribers. Nonetheless, guidelines for the prevention of corticosteroids toxicity are scarce, and the implementation of protective measures by prescribers is heterogenous. Hence, corticosteroids related complications entail a significant morbidity, which, importantly, could be largely prevented. We conducted therefore a systematic literature, through the Medline database, the Cochrane database and the grey literature until January 2021. After recalling the history of the discovery of corticosteroid therapy and its main pharmacological properties, we present the various complications associated with long-term corticosteroid therapy, and discuss the relevance of the preventive measures that may be proposed in daily practice in the light of available scientific evidence. This work highlights the importance of multidisciplinary follow-up, but above all of a thorough screening of the risk factors of complications at treatment initiation, and of a repeated evaluation of the complications all along the treatment course, in order to reduce the significant burden of morbidity associated with long-term corticosteroid therapy and to improve patient quality of life.

Effets indésirables de la corticothérapie orale au long cours. La corticothérapie systémique est utilisée depuis plus de 70 ans et reste la pierre angulaire du traitement de nombreuses affections. Ses effets indésirables sont nombreux et, pour la plupart, bien connus. Pour autant, les recommandations concernant leur prévention sont parfois manquantes, et souvent hétérogènes, y compris dans leur mise en œuvre par les prescripteurs. De ce fait, les complications induites par la corticothérapie sont à l'origine d'une morbidité importante, la plupart du temps évitables. Nous avons donc réalisé une revue systématique de la littérature, à travers les bases Medline, Cochrane et la littérature grise, jusqu'à janvier 2021. Après avoir rappelé l'histoire de la découverte de la corticothérapie et ses principales caractéristiques pharmacologiques, nous présentons les différentes complications associées à une corticothérapie au long cours et les mesures de prévention disponibles, en discutant leur efficacité et leur pertinence à la lumière des recommandations actuelles ou, à défaut, des dernières données scientifiques disponibles. Ce travail met en évidence l'importance du suivi multidisciplinaire des patients traités par corticothérapie systémique au long cours, mais surtout celle d'un dépistage préalable des facteurs associés à la survenue de complications et de réévaluations répétées de ces complications sous traitement, afin de diminuer le poids très important de la morbidité qui y est associée et ainsi d'améliorer la qualité de vie des patients.