Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene.

Osteoporosis is a skeletal disorder characterized by abnormal bone microarchitecture and low bone mineral density (BMD), responsible for an increased risk of fractures and skeletal fragility. It is a common pathology of the aging population. However, when osteoporosis occurs in children or young adults, it strongly suggests an underlying genetic etiology. Over the past two decades, several genes have been identified as responsible for this particular kind of considered monogenic early-onset osteoporosis (EOOP) or juvenile osteoporosis, the main ones being COL1A1, COL1A2, LRP5, LRP6, WNT1, and more recently PLS3. In this study, the objective was to characterize a large cohort of patients diagnosed with primary osteoporosis and to establish its diagnosis yield. The study included 577 patients diagnosed with primary osteoporosis and its diagnosis yield was established. To this end, next-generation sequencing (NGS) of a panel of 21 genes known to play a role in bone fragility was carried out. A genetic etiology was explained in about 18% of cases, while the others remain unexplained. The most frequently identified gene associated with EOOP is LRP5, which was responsible for 8.2% of the positive results (47 patients). As unexpected, 17 patients (2.9%) had a variant in PLS3 which encodes plastin 3. Alterations of PLS3 are associated with dominant X-linked osteoporosis, an extremely rare disease. Given the rarity of this disease, we focused on it. It was observed that males were more affected than females, but it is noteworthy that three females with a particularly severe phenotype were identified. Of these three, two had a variant in an additional gene involved in EOP, illustrating the probable existence of digenism. We significantly increase the number of variants potentially associated with EOOP, especially in PLS3. The results of our study demonstrate that molecular analysis in EOOP is beneficial and useful.

The Causes of Hypo- and Hyperphosphatemia in Humans.

Phosphate homeostasis involves several major organs that are the skeleton, the intestine, the kidney, and parathyroid glands. Major regulators of phosphate homeostasis are parathormone, fibroblast growth factor 23, 1,25-dihydroxyvitamin D, which respond to variations of serum phosphate levels and act to increase or decrease intestinal absorption and renal tubular reabsorption, through the modulation of expression of transcellular transporters at the intestinal and/or renal tubular level. Any acquired or genetic dysfunction in these major organs or regulators may induce hypo- or hyperphosphatemia. The causes of hypo- and hyperphosphatemia are numerous. This review develops the main causes of acquired and genetic hypo- and hyperphosphatemia.

High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults.

Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described.

Acute anterior uveitis in spondyloarthritis: a monocentric study of 301 patients.

OBJECTIVES: To assess the cumulative incidence of uveitis in spondyloarthritis (SpA) and its associated factors and to evaluate the effect of DMARD treatment on uveitis in a real-life setting. METHODS: A cross-sectional monocentric observational study (COSPA) was conducted. Patients with definite SpA underwent a face-to-face interview. General data and specific data concerning uveitis were collected. Cumulative incidence of uveitis flares was estimated by Kaplan-Meier survival curves. Factors associated with uveitis were determined by Cox analysis. Treatment effectiveness was evaluated by comparing the number of uveitis flares before/after treatment using Wilcoxon test. RESULTS: In total, 301 patients were included, 186 (61.8%) were men, with mean age and disease duration of 44.8 (±13.6) and 16.8 (±11.9) years, respectively. Among them, 82 (27.2%) had at least one uveitis flare. Prevalence of uveitis at the time of SpA diagnosis was 11.5 % (±1.9%) and increased over time to reach 39.3% (±4.1%) 20 years after diagnosis. HLA B27 positivity and heel pain were independently associated with uveitis (HR [IC 95%] = 4.5 [1.3-15.2] and 1.8 [1.1-2.9], respectively). A significant reduction in the number of uveitis before/after treatment was observed in patients treated with anti TNF monoclonal antibodies (n=27), (1.83 (±4.03) vs. 0.41 (±1.22), p=0.002), whereas it was not with etanercept (n=19), (0.44 (±0.70) and 0.79 (±1.36), p=NS). CONCLUSIONS: Prevalence of uveitis in SpA seems to increase with disease duration and seems more likely to appear with HLA B27 positivity and heel pain. Anti-TNF monoclonal antibodies seemed to be more effective in the reduction of uveitis flares.

Pre-, post- or no acidification of urine samples for calcium analysis: does it matter?

Background Measuring 24 h-urine calcium concentration is essential to evaluate calcium metabolism and excretion. Manufacturers recommend acidifying the urine before a measurement to ensure calcium solubility, but the literature offers controversial information on this pre-analytical treatment. The objectives of the study were (1) to compare pre-acidification (during urine collection) versus post-acidification (in the laboratory), and (2) to evaluate the impact of acidification on urinary calcium measurements in a large cohort. Methods We evaluated the effects of pre- and post-acidification on 24-h urine samples collected from 10 healthy volunteers. We further studied the impact of acidification on the calcium results for 567 urine samples from routine laboratory practice, including 46 hypercalciuria (≥7.5 mmol/24 h) samples. Results Calciuria values in healthy volunteers ranged from 0.6 to 12.5 mmol/24 h, and no statistical significance was found between non-acidified, pre-acidified and post-acidified conditions. A comparison of the values (ranging from 0.21 to 29.32 mmol/L) for 567 urine samples before and after acidification indicated 25 samples (4.4%) with analytical differences outside limits of acceptance. The bias observed for these deviant values ranged from -3.07 to 1.32 mmol/L; no patient was re-classified as hypercalciuric after acidification, and three patients with hypercalciuria were classified as normocalciuric after acidification. These three deviant patients represent 6.5% of hypercalciuric patients. Conclusions Our results indicate that pre- and post-acidification of urine is not necessary prior to routine calcium analysis.

Prevalence and clinical characteristics of psoriasis in spondyloarthritis: a descriptive analysis of 275 patients.

OBJECTIVES: To assess the prevalence of psoriasis among a cohort of patients with spondyloarthritis (SpA), to describe the clinical characteristics of psoriasis and associations with other manifestations. METHODS: This is a retrospective single-centre observational study. The patients were diagnosed with definite SpA (expert opinion), either axial or peripheral. Each patient underwent a direct interview by a physician. The data regarding history of psoriasis and its clinical characteristics were collected. Univariate and multivariate analyses of patients with versus without psoriasis were carried out. RESULTS: In all, 275 SpA patients were assessed: mean disease duration 16.7±11.8 years, 61.4% were men, 69.1% were diagnosed as axial SpA and 17.8% as peripheral SpA. In all, 84 patients (30.5%) had present or past psoriasis. The prevalence of psoriasis was high whatever the clinical presentation. Psoriasis was present before or concomitantly to diagnosis of SpA in 59/84 patients (70.2%). The most common types of psoriasis were plaque (66.7% of patients with psoriasis) and scalp psoriasis (65.5%). Other localisations were not rare, including palmoplantar pustulosis (20.2%) or nail psoriasis (19.1%). Patients with versus without psoriasis differed only through a lower proportion of radiological sacroiliitis (57.5% vs. 81.3 %, p<0.001). CONCLUSIONS: With a prevalence of 30.5%, i.e. ten times higher than in the general population, this study confirms that psoriasis is a frequent and early manifestation in SpA and that a systematic search for psoriasis (e.g. scalp) is relevant in SpA for clinical practice, whatever the clinical presentation of SpA.

A candidate gene study identifies a haplotype of CD2 as novel susceptibility factor for systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is a rare autoimmune disease (AID) with a complex genetic etiology. Evidence for a shared pathogenesis across AIDs is given by the well-known pleiotropism of autoimmune genes. Recently, several unbiased approaches have identified an association between polymorphisms of the CD2 gene, and rheumatoid arthritis (RA) susceptibility. The objective of this study was to investigate whether CD2 polymorphisms are associated with SSc. METHODS: Two SNPs of CD2, rs624988 and rs798036, were genotyped in a total of 1,786 SSc patients and 2,360 healthy individuals from two European populations (France and Italy). Meta-analyses were performed to assess whether an association exists between CD2 polymorphisms or haplotypes and SSc or its main subtypes. RESULTS: The combined analyses revealed an association between the rs624988 A allele and SSc susceptibility: padj=0.023, OR=1.14 (95%CI 1.04-1.25). Single marker analysis did not reveal any association between rs798036 and SSc. Haplotype analysis identified that the A-T haplotype, previously described in RA, was associated with higher susceptibility for SSc (padj=0.029, OR=1.14, 95%CI 1.04-1.25) and with the positive anti-centromere antibody sub-group of SSc patients (padj=0.009, OR=1.19 95%CI 1.07-1.32). Genotype-mRNA expression correlations revealed that the CD2 risk haplotype was associated with decreased CD2 mRNA expression in SSc patients. CONCLUSIONS: Our study establishes CD2 as a new susceptibility factor for SSc, in a European Caucasian population, confirming the sharing of autoimmune risk factors by SSc and RA.

Choosing the tool for osteoporosis risk prediction.

PURPOSE OF REVIEW: Predicting fracture risk is a major challenge because it allows the prevention of major osteoporotic fracture in high-risk populations. With the aging of the population, this matter will become of even greater importance. In recent years, novel clinical, biochemical, and imaging tools have been developed to improve the assessment of fracture risk. RECENT FINDINGS: The present review summarizes novel clinical strategies, Dual energy X-ray absorptiometry (DXA)-derived tools, imaging techniques, and biochemical markers that have been developed recently to improve fracture risk prediction. SUMMARY: DXA and clinical fracture risk prediction tools are preferential markers of fracture risk. Clinical fracture risk alone might be used if DXA facilities are unavailable. The fracture risk assessment tool may be used in osteoporosis consultation in many countries. Other tools may be used soon after more studies are performed, particularly trabecular bone score, quantitative ultrasound, bone turnover markers. Specific factors for example falls, hip axis length, vertebral fracture assessment could be used in individual patients. This may significantly improve the clinical decision-making.

Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis.

OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88x10(-2), OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89x10(-2), OR=1.13; p=1.69x10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00x10(-4), OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.

A regulatory variant in CCR6 is associated with susceptibility to antitopoisomerase-positive systemic sclerosis.

OBJECTIVE: Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. METHODS: Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA-associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. RESULTS: Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [P(adj)] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, P(adj) = 1.5 × 10(-3) and OR 1.32, 95% CI 1.17-1.48, P(adj) = 9.0 × 10(-5), respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. CONCLUSION: The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc.

Trabecular bone score (TBS) in Cushing's disease: TBS gain after hypercortisolism normalization.

CONTEXT: Hypercortisolism frequently induces trabecular bone loss, more pronounced at the lumbar spine, resulting in osteoporosis, and thus an increase in fracture risk. Several studies have shown bone mass recovery in patients with Cushing's disease (CD) after treatment. OBJECTIVE: To examine treatment effects on TBS (trabecular bone score) in addition to aBMD (areal bone mineral density) in a cohort of patients with CD. DESIGN AND SETTING: Single-center retrospective longitudinal study in patients diagnosed with CD and successfully treated following surgery and/or medical treatment. PATIENTS: We included 31 patients with median age and BMI (body mass index) of 37.7 [28.4;43.3] years old and 27.7 [25.8;30.4] kg/m2, respectively. Median 24 h urinary cortisol before treatment was 213.4 [168.5;478.5] µg/24 h. All subjects were completely biochemically controlled or cured after treatment. MAIN OUTCOME MEASURES: aBMD and TBS were evaluated at AP Spine (L1-L4) with DXA prodigy (GE-Lunar), QDR 4500 (Hologic), and TBS iNsight® (Med-Imaps) before and after treatment. RESULTS: Absolute TBS and aBMD gains following cure of CD were significant (p < 0.0001, and p < 0.001, respectively). aBMD and TBS increased by +3.9 and 8.2 % respectively after cure of CD. aBMD and TBS were not correlated before (p = 0.43) and after treatment (p = 0.53). Linear regression analyses showed that TBS gain was independent of baseline BMI and that low TBS at baseline was predictive of TBS gain after treatment. CONCLUSION: The more significant improvement of microarchitecture assessed by TBS than aBMD and the absence of correlation between TBS and aBMD suggest that TBS may be an adequate marker of bone restoration after cure of CD. To support this conclusion, future studies with larger sample sizes and longer follow-up periods should be carried out.

Clinical spectrum of rare bone fragility disorders and response to bisphosphonate treatment: a retrospective study.

Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85-90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.In this study, we investigated the clinical characteristics of 38 patients with a bone fragility disorder that had variants in non-COL1A1/COL1A2 genes in order to study genotype-phenotype correlations, as the natural history of these rare forms is still not well known. We then studied the usefulness of bisphosphonate treatment by evaluating the effects on LS BMD, annual non-vertebral fracture rate, bone turnover markers and height. This study enabled us to better define the natural history of patients with non-COL1 pathogenic variants. Patients with CRTAP and TMEM38B variants consistently had a prenatal presentation with a short (<3rd p) and bowed femur. Importantly, this prenatal involvement does not predict the postnatal severity of the disease. Regarding treatment by bisphosphonates, all patients showed a significant increase in LS BMD while treated and this increase was dependent on the dose received. The increase in LS BMD also translated in a reduction of fracture rate during treatment. Finally, our study showed that the earlier bisphosphonates are initiated, the greater the fracture rate is reduced.

Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review.

CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.

Fatigue in spondyloarthritis: a marker of disease activity. A cross-sectional study of 266 patients.

OBJECTIVES: Fatigue is an important aspect of spondyloarthritis (SpA). However the influencing factors of fatigue in SpA are unclear. The objective of this study was to explore if fatigue is related to disease activity or to patient characteristics. METHODS: This was a retroelective observational study (Cochin COSPA study) in one tertiary-referral centre. The primary outcome was fatigue, evaluated on a 0-100mm Visual Analogue Scale (VAS). The covariates were demographic characteristics, disease subtype (axial vs. peripheral) and disease-related factors, e.g. Bath Disease Activity Index (BASDAI), patient global assessment (VAS), Bath Functional Index (BASFI). To explain fatigue, univariate then multivariate logistic regressions were conducted (with fatigue analysed as above or below 50 mm), as well as multiple linear regressions with the different covariates. RESULTS: Two hundred and sixty-six SpA patients were analysed. Sixty-one percent were male; mean age and disease duration were 44.5±13.5 years and 16.8±11.7 years, respectively. Mean VAS fatigue was 49.3±32.7mm; 49.6% of patients had fatigue VAS>50mm. Logistic regression showed high fatigue was associated with disease: BASDAI and BASFI (p<0.0001), as well as female gender (p=0.025) and aerobic exercise (p=0.005), but there was no difference in the subtypes of SpA. In multivariate analysis, the single factor explaining fatigue was patient global assessment (p<0.001 and odds ratio =1.35). By linear regression, demographic variables explained 2.8% of the variance, whereas disease characteristics and activity explained 44.6%. CONCLUSIONS: Fatigue levels were high in SpA patients whatever the subtype and appeared more strongly related to the disease than to patient-related variables, thus confirming its usefulness as an outcome measure.

Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity.

OBJECTIVE: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) share some pathophysiologic bases as evidenced by individual and familial polyautoimmunity and common susceptibility genetic factors. With regard to the latter, there has been a recent shift from the "common variant" to the "rare variant" paradigm, since rare variants of TNFAIP3 and TREX1 with large effect sizes have recently been discovered in SLE. The present study was undertaken to investigate whether rare variants of TNFAIP3 and TREX1 are also associated with SSc. METHODS: TREX1 single-nucleotide polymorphisms (SNPs) rs3135946, rs7626978, rs3135943, and rs11797 and TNFAIP3 SNPs rs9494883, rs72063345, rs5029939, rs2230926, rs117480515, and rs7749323 were genotyped in a discovery set (985 SSc patients and 1,011 controls), and replication analysis of the most relevant results was performed in a second set (622 SSc patients and 493 controls). RESULTS: No association between TREX1 variants and SSc was observed. For TNFAIP3, we first demonstrated that a low-frequency variant, rs117480515, tagged the recently identified TT>A SLE dinucleotide. In the discovery sample, we observed that all tested TNFAIP3 variants were in linkage disequilibrium and were associated with SSc and various SSc subsets, including the polyautoimmune phenotype. We subsequently genotyped rs117480515 in the replication sample and found it to be associated solely with the SSc polyautoimmune subset (odds ratio 3.51 [95% confidence interval 2.28-5.41], P = 8.58 × 10(-9) ) in the combined populations. Genotype-messenger RNA (mRNA) expression correlation analysis revealed that the TNFAIP3 rs117480515 risk allele was associated with decreased mRNA expression. CONCLUSION: The present findings establish the TNFAIP3 locus as a susceptibility factor for the subset of SSc with a polyautoimmune phenotype. Our results support the implication of rare/low-frequency functional variants and the critical role of A20 in autoimmunity.

FCH-PET/CT in Primary Hyperparathyroidism With Discordant/Negative MIBI Scintigraphy and Ultrasonography.

CONTEXT: The contribution of [18F]F-fluorocholine (FCH)-positron emission tomography (PET)/computed tomography (CT) in normocalcemic primary hyperparathyroidism (nPHPT) remains unknown. OBJECTIVE: To evaluate the sensitivity and specificity of FCH-PET/CT in a cohort of osteoporotic patients with nPHPT and discordant or negative [99mTc]Tc-sestamibi scintigraphy and ultrasonography who all underwent parathyroidectomy (PTX). DESIGN: Longitudinal retrospective cohort study in patients referred for osteoporosis with mild biological primary hyperparathyroidism. SETTING: Tertiary referral center with expertise in bone metabolism and surgical management of hyperparathyroidism. PATIENTS: Among 109 patients with PHPT analyzed, 3 groups were individualized according to total serum calcium (tCa) and ionized calcium (iCa): 32 patients with hypercalcemia (HtCa group), 39 patients with normal tCa and elevated iCa (NtCa group), and 38 patients with both normal tCa and iCa (NiCa). All patients had biochemical follow-up confirming or not the success of PTX. MAIN OUTCOME MEASURES: To evaluate the performance of FCH-PET/CT in terms of sensitivity and specificity, and to compare with first-line imaging procedures in the setting of nPHPT. RESULTS: The sensitivity of FCH-PET/CT was 67% in the hypercalcemic group, 48% in the NtCa group (P = .05 vs HtCa), and 33% in the NiCa group (P = .004 vs HtCa). Specificity ranged from 97% to 99%. FCH-PET/CT was positive in 64.3% of patients with negative conventional imaging, with biochemical resolution after PTX in 77.8% of patients. Triple negative imaging was observed in 20 patients, with PHPT resolution in 85% of these patients. CONCLUSION: This study highlights the contribution of FCH-PET/CT in a well-phenotyped cohort of normocalcemic patients with discordant or negative findings in [99mTc]Tc-sestamibi scintigraphy and ultrasonography. However, negative imaging in nPHPT does not rule out the possibility of surgical cure by an experienced surgeon.

TGFß receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients.

INTRODUCTION: Systemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFß) receptor genes strongly contribute to idiopathic and familial PAH. OBJECTIVE: To explore the genetic bases of SSc-PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFß receptor family members. MATERIALS AND METHODS: TGFß receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc-PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a first set of 824 French Caucasian SSc patients (including 54 SSc-PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc-PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network. RESULTS: No mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc-PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc-PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07. CONCLUSIONS: This study demonstrates the lack of association between these TGFß receptor gene polymorphisms and SSc-PAH using both sequencing and genotyping methods.

Assessment of work instability in spondyloarthritis: a cross-sectional study using the ankylosing spondylitis work instability scale.

OBJECTIVES: Work status is an important outcome in SpA. The objective was to assess work instability and its determinants in a cohort of patients with SpA, using the AS-work instability scale (AS-WIS). METHODS: We performed a cross-sectional monocentre study. Patients were definite SpA patients with paid work. Work instability was measured by the AS-WIS. Its determinants were assessed by correlations with SpA scores (BASDAI, BASFI and patient's global assessment) and patients with low work instability (AS-WIS score < 11) were compared with those with moderate to high instability, through backward logistic regression. RESULTS: In all, 156 patients were assessed: mean (s.d.) age 41 (11) years, mean disease duration 15 (11) years; 71 (45.5%) were on TNF blockers. The mean AS-WIS score was 9.5 (5.5); 55 (35%) patients had moderate and 8 (5%) patients had high work instability. Correlations of the AS-WIS score with SpA scores were significant but moderate (BASDAI R = 0.42, BASFI R = 0.41, patient's global assessment R = 0.53; P < 0.0001). In multivariate analysis, high patient's global assessment was the only element associated with moderate to high work instability; demographic characteristics and treatments were not significant elements. CONCLUSION: Work instability was found to be high and its main determinant was patient's global assessment. The predictive validity of the AS-WIS in terms of job retention should be further assessed.

Prevalence and clinical characteristics of dactylitis in spondylarthritis: a descriptive analysis of 275 patients.

OBJECTIVES: Dactylitis is a common but little studied feature of spondylarthritis (SpA). Our objective was to assess the prevalence of dactylitis among a cohort of patients with spondylarthritis in a tertiary care centre and to describe the clinical characteristics of dactylitis. METHODS: This was a prospective single centre observational study carried out in 2010. The patients included had been diagnosed as having definite SpA based on Amo's criteria. Each patient was interviewed by a physician. The data collected included prevalence of dactylitis and its clinical characteristics, effectiveness of the different treatments, and association with severe manifestations of SpA, and analysed by descriptive analysis. RESULTS: 275 consecutive SpA patients were assessed: mean age 43.2±13.5 years, mean disease duration 14.0±11.8 years, 169 (61.4%) were men. In all, 59 patients (21.5%) suffered from SpA-associated dactylitis. The localisation of dactylitis was toes in 46 patients (78.0%) and/or fingers in 25 patients (42.4%). The most frequent localisations were the second toe and the second finger. Dactylitis was the first symptom of SpA in 14 patients (5.1%), and 28.8% (n=17) of dactylitis appeared within the first 5 years of disease. Dactylitis was present in 35.1% (n=13) of patients with undifferenciated SpA and in 30.6% (n=15) of patients with psoriatic arthritis. It was significantly associated with history of peripheral arthritis or heel pain. In our population, there was no correlation between dactylitis and HLA B27 status or sex and it was not a marker of severity of disease. CONCLUSIONS: Dactylitis is a frequent manifestation in SpA (21.5%) particularly in peripheral disease and it may be the first manifestation of the disease with localisation being more frequent in the toes.

Heel pain in spondyloarthritis: results of a cross-sectional study of 275 patients.

OBJECTIVES: Heel pain is a common but poorly studied feature of spondyloarthritis (SpA). The aims of this study were to assess the prevalence and clinical features of heel pain in a cohort of patients with SpA. METHODS: This was a retrolective single centre observational study in 2010. Patients with SpA as defined by Amor's criteria were recruited. The data collected were: demographic and disease characteristics, history of heel pain, age at first heel pain, localisation, nature and intensity of pain and treatments. The analyses were descriptive. RESULTS: A total of 275 SpA patients (mean age 44.6±13.5 yrs, mean disease duration 16.7±11.8 yrs, 61.5% men) were assessed. A history of heel pain was reported in 130 patients (47.1%), and was the first symptom of SpA in 15.7% of all patients. Heel pain was frequent in both axial (89/201, 44.3%) and peripheral disease (27/56, 48.2%). Distribution was more frequently inferior (88, 69.3%) than posterior (61, 48.0%) (p<0.0001), and frequently bilateral: simultaneously (41.9%) rather than alternatively (29.1%) (p=0.03). Main clinical symptoms were: morning pain on weight bearing (83.6%), but also night pain (34.4%), and/or patient-described swelling (24.2%). Heel pain was frequently recurrent (74.2%), intense (70.3%), source of a limp (71.6%), and often resistant to non-steroidal anti-inflammatory drugs (NSAIDs) (54/108, 50%). Tumour necrosis factor blockers were efficacious on heel pain in 72/94 (76.6%) of cases. CONCLUSIONS: This study confirmed heel pain as a frequent symptom in both axial and peripheral SpA. It occurred early in the disease course and it was frequently recurrent and resistant to NSAIDs.