Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.

Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults.

BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.

Do subjective components of disease activity contribute to heterogeneity in opioid prescriptions in inflammatory rheumatic diseases? Results from ESPOIR and DESIR cohorts.

OBJECTIVES: To determine whether subjective components of disease activity are associated with heterogeneity in opioid prescription in inflammatory rheumatic diseases (IRDs) after accounting for objective inflammatory markers. METHODS: Data from two prospective observational cohorts of early IRDs (ESPOIR for rheumatoid arthritis (RA) and DESIR for spondyloarthritis (SpA)) were included. Opioid prescription duration (converted to monthly binary opioid prescription), disease activity (Disease activity score 28 (DAS28) for RA; Axial spondyloarthritis disease activity score-C-reactive protein (ASDAS-CRP) for SpA) and its components were measured respectively at 13 and 9 occasions spanning 10- and 6-years of follow-up. Group-based trajectory modelling defined opioid-prescription trajectories and mixed-models characterised the evolution of disease activity and its subjective components by opioid-prescription trajectories. RESULTS: Four distinct opioid-prescription trajectories: no/low (60.5% and 54.3%), declining (14.7% and 15.8%), augmenting (11.9% and 10.7%), and persistent (12.9% and 19.1%) were identified in RA and SpA respectively (60% were prescribed opioids at least once). Those with regular opioid prescriptions (up to 30%) are often older, less educated, have higher BMI and worse disease. No/low trajectory was the reference for examining evolution of disease activity and subjective components (n=810 RA, n=679 SpA). In IRDs, consistently higher disease activity throughout follow-up were seen with persistent (DAS28(ß=0.4-0.8); ASDAS-CRP(ß=0.4-0.6)), and augmenting (DAS28(ß=0.2-0.5); ASDAS-CRP(ß=0.3-0.6)) trajectories and until 3- or 4-years of follow-up (DAS28(ß=0.3-0.4); ASDAS-CRP(ß=0.2-0.3)) with declining trajectory. Likewise, despite accounting for objective inflammation, subjective components had worse scores over follow-up in augmenting and persistent trajectory. CONCLUSIONS: Non-inflammatory pain mechanisms amplify subjective outcomes, thus, worsening composite measures like disease activity.

Aortic Sarcoma Patients with Bone Metastasis.

BACKGROUND: Metastases to the bone of aortic sarcoma include osteolytic and nonosteolytic lesions. This study aims to review the clinical symptoms, the sites, and diagnostic methods of bone metastases and to compare the osteolytic and nonosteolytic metastases of patients with aortic sarcoma. METHODS: A systematic search was conducted in PubMed and scientific journals published from 1972 to 2022. Database included reports of aortic sarcomas with bone metastasis published in English and in French. Characteristics of patients were analyzed with chi-square test or Fisher's exact test between lytic and sclerotic bone metastases. RESULTS: In 29 patients with bone destruction, the symptoms of low back pain and claudication were observed in 10 (34.5%) and 9 cases (31%), respectively. Acute ischemia of the legs and arms accounted for 7 cases (24.1%). There were 4 cases with hypertension (13.8%) and 5 cases with chest pain or abdominal pain or epigastric pain (17.2%). Metastases to the vertebrae, pelvis, and femur were observed in 14 (48.3%), 12 (41.4%), and 11 cases (37.9%), respectively. Osteolytic lesions were detected at the time of diagnosis in 16/29 (55.2%) cases. In 27 aortic sarcoma patients with sclerotic bone metastases, symptoms of hypertension were observed in 10 (37.0%), of back pain in 7 (25.9%), of chest pain or abdominal pain in 5 cases (18.5%). Acute ischemia of the leg occurred in 6 cases (22.2%). Metastases to the vertebrae, bone, pelvis, and femur were observed in 10 (37.0%), 9 (33.3%), 7 (25.9%), and 6 cases (22.2%), respectively. The sign of claudication and methods for detected bone destruction by X-rays were the difference between osteolytic and nonosteolytic metastases of aortic sarcoma (P = 0.019; P = 0.001), respectively. CONCLUSIONS: Back pain is a common symptom of aortic sarcoma with bone metastasis. The sign of intermittent claudication is the difference between osteolytic and nonosteolytic metastases of aortic sarcoma. Bone destruction occurred in all bones, but mainly in vertebrae, pelvis, and femur. Methods for detection of bone destruction are mainly by X-rays or computed tomography (CT). Bone destruction was an important sign to detect aortic sarcoma. Sclerotic bone metastases occurred mainly in vertebrae, pelvis, bone, and femur. The detection of sclerotic bone metastases is based on magnetic resonance imaging, positron emission tomography/CT, and autopsy.

Efficacy and management of tocilizumab in polymyalgia rheumatica: results of a multicenter retrospective observational study.

OBJECTIVES: The efficacy of anti-IL6 receptors such as Tocilizumab (TCZ) was demonstrated in patients with Polymyalgia Rheumatica (PMR) in two recent randomized controlled trials. The objective of this multicentre retrospective study was to assess the efficacy of TCZ in PMR patients requiring GC-sparing treatment, as well as different strategies for TCZ withdrawal. METHODS: We conducted a multicentre study in French tertiary health care departments for patients with PMR. PMR patients receiving off-label TCZ between 2015 and 2022 were included. The primary end point was the proportion of patients tapering to glucocorticoids (GCs) ≤5mg/day 6 months after the first TCZ infusion. The secondary endpoints were the proportion in whom GC was discontinued during follow-up, and the proportion of patients in whom TCZ was discontinued. RESULTS: Fifty-three PMR patients were included. Thirty-one (31) patients suffered from active PMR despite csDMARDs. GCs were ≤5mg/day in 77% of the patients (95% confidence interval [CI95%]: 36-89) at 6 months, and in 97% of the patients at 12 months. Six and 12 months after the first TCZ infusion, the proportions of GC-free patients were 22.5% (CI95%: 12.7-37.8) and 58.3% (CI95%: 43.2-74.1), respectively. Among TCZ withdrawal strategies, TCZ infusion spacing and TCZ dose reduction were more successful (success in 87% and 79% of attempts, respectively) than TCZ discontinuation (success in 52% of attempts; p= 0.012 and p= 0.039, respectively). CONCLUSION: In GC-dependent PMR patients, treatment with TCZ led to a drastic decrease in GC dose and remission of PMR. TCZ dose reduction or TCZ infusion spacing are good options to consider in TCZ withdrawal.

Effectiveness of Geniculate Artery Embolization for Chronic Pain after Total Knee Replacement-A Pilot Study.

PURPOSE: To evaluate the efficacy and safety of embolization of hyperemic synovial tissue for the treatment of persistent pain after total knee arthroplasty (TKA). MATERIALS AND METHODS: Twelve patients with persistent pain after TKA were enrolled in this prospective, single-center pilot study. Genicular artery embolization (GAE) was performed using 75-µm spherical particles. The patients were assessed using a 100-point Visual Analog Scale (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline and 3 and 6 months thereafter. Adverse events were recorded at all time points. RESULTS: A mean of 1.8 ± 0.8 abnormal hyperemic genicular arteries were identified and embolized, with a median volume of diluted embolic material of 4.3 mL in all 12 (100%) patients. The mean VAS score on walking improved from 73 ± 16 at baseline to 38 ± 35 at the 6-month follow-up (P < .05). The mean KOOS pain score improved from 43.6 ± 15.5 at baseline to 64.6 ± 27.1 at the 6-month follow-up (P < .05). At the 6-month follow-up, 55% and 73% of the patients attained a minimal clinically important change in pain and quality of life, respectively. Self-limited skin discoloration occurred in 5 (42%) patients. The VAS score increased by more than 20 immediately after embolization in 4 (30%) patients, who required analgesic treatment for 1 week. CONCLUSION: GAE is a safe method of treating persistent pain after TKA that demonstrates potential efficacy at 12 months.

Machine-learning derived algorithms for prediction of radiographic progression in early axial spondyloarthritis.

OBJECTIVES: To compare machine learning (ML) to traditional models to predict radiographic progression in patients with early axial spondyloarthritis (axSpA). METHODS: We carried out a prospective French multicentric DESIR cohort study with 5 years of follow-up that included patients with chronic back pain for <3 years, suggestive of axSpA. Radiographic progression was defined as progression at the spine (increase of at least 1 point of mSASSS scores/2 years) or at the sacroiliac joint (worsening of at least one grade of the mNY score between 2 visits). Statistical analyses were based on patients without any missing data regarding the outcome and variables of interest (295 patients).Traditional modelling: we performed a multivariate logistic regression model (M1); then variable selection with stepwise selection based on Akaike Information Criterion (stepAIC) method (M2), and Least Absolute Shrinkage and Selection Operator (LASSO) method (M3).ML modelling: using "SuperLearner" package on R, we modelled radiographic progression with stepAIC, LASSO, random forest, Discrete Bayesian Additive Regression Trees Samplers (DBARTS), Generalized Additive Models (GAM), multivariate adaptive polynomial spline regression (polymars), Recursive Partitioning And Regression Trees (RPART) and Super Learner. Accuracy of these models was compared based on their 10-fold cross-validated AUC (cv-AUC). RESULTS: 10-fold cv-AUC for traditional models were 0.79 and 0.78 for M2 and M3, respectively. The three best models in the ML algorithms were the GAM, the DBARTS and the Super Learner models, with 10-fold cv-AUC of: 0.77, 0.76 and 0.74, respectively. CONCLUSIONS: Two traditional models predicted radiographic progression as good as the eight ML models tested in this population.

The Association between Oxytocin and Lower Limb Osteoarthritis: A Prospective Cohort Study.

Oxytocin (OT), a neuropeptide best known for its role in emotional and social behaviors, has been linked to osteoarthritis (OA). This study aimed to investigate the serum OT level in hip and/or knee OA patients and to study its association with disease progression. Patients from the KHOALA cohort with symptomatic hip and/or knee OA (Kellgren and Lawrence (KL) scores of 2 and 3) and follow-up at 5 years were included in this analysis. The primary endpoint was structural radiological progression, which was defined as an increase of at least one KL point at 5 years. Logistic regression models were used to estimate the associations between OT levels and KL progression while controlling for gender, age, BMI, diabetes and leptin levels. Data from 174 hip OA patients and 332 knee OA patients were analyzed independently. No differences in OT levels were found between the 'progressors' and 'non-progressors' groups among the hip OA patients and knee OA patients, respectively. No statistically significant associations were found between the OT levels at baseline and KL progression at 5 years, the KL score at baseline or the clinical outcomes. Higher structural damage at baseline and severe structural progression of hip and knee osteoarthritis did not appear to be associated with a low serum OT level at baseline.

Management and outcome of native joint septic arthritis: a nationwide survey in French rheumatology departments, 2016-2017.

OBJECTIVES: To describe current management and outcome of native joint septic arthritis (NJSA) in French rheumatology departments. METHODS: For this retrospective, nationwide multicentric study, 127 French rheumatology departments were contacted to report up to 12 cases of NJSA that occurred between 1 January 2016 and 31 December 2017. Characteristics, diagnosis procedures, therapeutic management and outcome were recorded. RESULTS: Overall, 362 patients were included (mean age 64.0±18.6 years, median Charlson comorbidity index 3.5 (0-14)). Knee was the most frequent site (n=160 (38.9%)), and Staphylococcus sp (n=185 (51.4%)), the most frequent pathogen. All patients received antibiotics for a mean duration of 46.8 (±22.0) days, including intravenous route for a mean of 17.2 (±15.4) days. Management was heterogeneous. Surgical procedure was performed in 171 (48.3%), joint immobilisation in 128 (43.8%). During follow-up, 91 (28.3%) patients have had serious complications and 28 (9.2%) of them died. Factors associated with 1-year mortality were age (OR 1.08, 95% CI 1.04 to 1.13; p<0.001), Charlson's index (OR 1.30, 95% CI 1.06 to 1.58; p=0.012), presence of bacteraemia (OR 4.02, 95% CI 1.35 to 11.99; p=0.008), antibiotic use in the previous 3 months (OR 3.32, 95% CI 1.11 to 9.87; p=0.029) and Staphylococcus aureus NJSA compared with Streptococcus sp. NJSA (OR 7.24, 95% CI 1.26 to 41.68, p=0.027). The complete recovery with no adverse joint outcome at 1 year was observed in n=125/278 patients (55.0%). CONCLUSION: Prognosis of NJSA remained severe with a high rate of morbimortality. Its management was very heterogeneous. This study highlights the importance of the new French recommendations, published after the completion of the study, in order to facilitate NJSA management.