Characterization of serum phosphate levels over time with intravenous ferric carboxymaltose versus placebo as treatment for heart failure with reduced ejection fraction and iron deficiency: An exploratory prospective substudy from HEART-FID.

AIMS: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. METHODS AND RESULTS: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. CONCLUSIONS: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF.

Inherited fibroblast growth factor 23 excess.

Syndromes of inherited fibroblast growth factor 23 (FGF-23) excess encompass a wide spectrum that includes X-linked hypophosphataemia (XLH), autosomal dominant and recessive forms of rickets as well as various syndromic conditions namely fibrous dysplasia/McCune Albright syndrome, osteoglophonic dysplasia, Jansen's chondrodysplasia and cutaneous skeletal hypophosphataemia syndrome. A careful attention to patient symptomatology, family history and clinical features, supported by appropriate laboratory tests will help in making a diagnosis. A genetic screen may be done to confirm the diagnosis. While phosphate supplements and calcitriol continue to be the cornerstone of treatment, in recent times burosumab, the monoclonal antibody against FGF-23 has been approved for the treatment of children and adults with XLH. While health-related outcomes may be improved by ensuring adherence and compliance to prescribed treatment with a smooth transition to adult care, bony deformities may persist in some, and this would warrant surgical correction.

Neurodevelopmental Outcome in Very Preterm Infants Randomised to Receive Two Different Standardised, Concentrated Parenteral Nutrition Regimens.

We have previously shown that increasing parenteral protein (target: 3.8 versus 2.8 g/kg/d) and energy (12% versus 10% glucose; 3.8 versus 2.8 g/kg/d) intake using a Standardised, Concentrated with Added Macronutrients Parenteral (SCAMP) nutrition regimen ameliorates early head growth failure in very-preterm infants (VPIs). We hypothesised that the SCAMP nutrition regimen would also improve neurodevelopmental outcome. The original double-blind randomised, controlled study (ISRCTN: 76597892) received ethical approval. VPIs were randomised to either start SCAMP or remain on the control regimen. The consent process included neurodevelopmental assessments (Bayley III), all of which were performed (blinded) at 2-3.5 years of corrected gestational age. Bayley III assessments were performed for 38/60 SCAMP survivors and 41/63 control survivors at means of (sd) 29.2 (3.7) and 20.0 (3.9) months, respectively. Motor, cognitive, language, and combined scores were all higher in the SCAMP intervention group, but none of the differences were statistically significant. Nutrient intake and biochemical monitoring data confirmed that protein/energy ratios were maintained in the SCAMP intervention group without increasing the incidence of hyperglycaemia, insulin treatment, or the derangement of plasma mineral/electrolyte levels. This study did not show a statistically significant improvement in neurodevelopmental outcome when administering higher parenteral protein/energy intakes despite optimal energy and mineral intakes.

The Impact of Moderate Hypophosphatemia on the Clinical Management of Primary Hyperparathyroidism.

Background and objective The impact of moderate hypophosphatemia (hypoP) on primary hyperparathyroidism (PHPT) and its use as an independent surgical criterion has not been adequately evaluated in the literature. In light of this, we conducted this study to address the scarcity of data on this topic. Methods We conducted a retrospective evaluation of data related to 164 (133 females and 31 males) patients with PHPT who met the criteria for inclusion in the study. HypoP, which is indicated by phosphorus (P) levels lower than 2.5 mg/dL, was found in 78 (47.5%) patients, and moderate hypoP (1-1.99 mg/dL) was found in 25 patients (15.2%). Results PHPT severity was worse in hypoP patients than non-hypoP patients, as evidenced by higher levels of mean serum calcium (12.9 ±1.0 mg/dL vs. 11.1 ±0.3 mg/dL respectively, p<0.001), parathormone (PTH) [median (interquartile range, IQR): 455.3 (455.3) ng/L vs. 124.0 (84.0) ng/L respectively, p<0.001] and mean 24-hour urinary calcium (414.6 ±168.5 mg/day vs. 291.5 ±161.4 mg/day respectively, p=0.026) as well as lower levels of mean BMI (25.6 ±3.9 kg/m2 vs. 29.0 ±4.0 kg/m2 respectively, p=0.18) and mean 25-hydroxy vitamin D3 (13.8 ±7.3 µg/L vs. 18.2 ±7.8 µg/L respectively, p=0.001). Among the whole study population as well as among patients with Ca levels <1.0 mg/dL according to the upper limit of normal, P level was determined to be an independent factor affecting the indication for surgical treatment [ß: -1.96,p=0.038, odds ratio (OR): 0.14, 95% confidence interval (CI): 0.02-0.89 and ß: -2.3, p=0.034, OR: 0.10, 95% CI: 0.12-0.84 respectively]. Conclusion We found a strong correlation between moderate hypoP and the severity of the biochemical manifestations of PHPT. In asymptomatic PHPT patients, moderate hypoP was predictive of surgical indication, independent of age and level of hypercalcemia.

De Novo Large Deletions in the PHEX Gene Caused X-Linked Hypophosphataemic Rickets in Two Italian Female Infants Successfully Treated with Burosumab.

Pathogenic variants in the PHEX gene cause rare and severe X-linked dominant hypophosphataemia (XLH), a form of heritable hypophosphatemic rickets (HR) characterized by renal phosphate wasting and elevated fibroblast growth factor 23 (FGF23) levels. Burosumab, the approved human monoclonal anti-FGF23 antibody, is the treatment of choice for XLH. The genetic and phenotypic heterogeneity of HR often delays XLH diagnoses, with critical effects on disease course and therapy. We herein report the clinical and genetic features of two Italian female infants with sporadic HR who successfully responded to burosumab. Their diagnoses were based on clinical and laboratory findings and physical examinations. Next-generation sequencing (NGS) of the genes associated with inherited HR and multiple ligation probe amplification (MLPA) analysis of the PHEX and FGF23 genes were performed. While a conventional analysis of the NGS data did not reveal pathogenic or likely pathogenic small nucleotide variants (SNVs) in the known HR-related genes, a quantitative analysis identified two different heterozygous de novo large intragenic deletions in PHEX, and this was confirmed by MLPA. Our molecular data indicated that deletions in the PHEX gene can be the cause of a significant fraction of XLH; hence, their presence should be evaluated in SNV-negative female patients. Our patients successfully responded to burosumab, demonstrating the efficacy of this drug in the treatment of XLH. In conclusion, the execution of a phenotype-oriented genetic test, guided by known types of variants, including the rarest ones, was crucial to reach the definitive diagnoses and ensure our patients of long-term therapy administration.

What is wrong in doing good?

Hypophosphataemia is a common side-effect in patients with iron deficiency anaemia treated with ferric carboxymaltose, which is not a class effect of all intravenous (IV) iron formulations. The report by Chu et al. shows that moderate and severe hypophosphataemia is common and can even require IV supplementation of phosphate with unknown long-term consequences. Commentary on: Chu et al. Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-a 3-year experience from a single institution in Singapore. Br J Haematol 2023;202:1199-1204.

Transition of patients with metabolic bone disease from paediatric to adult healthcare services: current situation and proposals for improvement.

BACKGROUND: There are currently no models for the transition of patients with metabolic bone diseases (MBDs) from paediatric to adult care. The aim of this project was to analyse information on the experience of physicians in the transition of these patients in Spain, and to draw up consensus recommendations with the specialists involved in their treatment and follow-up. METHODS: The project was carried out by a group of experts in MBDs and included a systematic review of the literature for the identification of critical points in the transition process. This was used to develop a questionnaire with a total of 48 questions that would determine the degree of consensus on: (a) the rationale for a transition programme and the optimal time for the patient to start the transition process; (b) transition models and plans; (c) the information that should be specified in the transition plan; and (d) the documentation to be created and the training required. Recommendations and a practical algorithm were developed using the findings. The project was endorsed by eight scientific societies. RESULTS: A total of 86 physicians from 53 Spanish hospitals participated. Consensus was reached on 45 of the 48 statements. There was no agreement that the age of 12 years was an appropriate and feasible point at which to initiate the transition in patients with MBD, nor that a gradual transition model could reasonably be implemented in their own hospital. According to the participants, the main barriers for successful transition in Spain today are lack of resources and lack of coordination between paediatric and adult units. CONCLUSIONS: The TEAM Project gives an overview of the transition of paediatric MBD patients to adult care in Spain and provides practical recommendations for its implementation.

Incidence and predictors of hypophosphataemia after ferric carboxymaltose use-A 3-year experience from a single institution in Singapore.

Ferric carboxymaltose (FCM) administration helps reduce transfusion requirements in the perioperative situation, which improves patient outcomes and reduces healthcare costs. However, there is increasing evidence of hypophosphataemia after FCM use. We aim to determine the incidence of hypophosphataemia after FCM administration and elucidate potential biochemical factors associated with the development of subsequent hypophosphataemia. A retrospective review of anonymised data of all FCM administrations in a single institution was conducted from August 2018 to August 2021. Each unique FCM dose administered was examined to assess its effect on Hb and serum phosphate levels within the subsequent 28 days from each FCM administration. Phosphate levels were repeatedly measured within the 28-day interval and the lowest phosphate level within that period was determined. Patients' serum phosphate levels within 28 days of FCM administration were compared against normal serum phosphate levels within 2 weeks before FCM administration. The odds ratios of various pre-FCM serum markers were calculated to elucidate potential biochemical predictors of post-FCM hypophosphataemia. In 3 years, a total of 1296 doses of FCM were administered to 1069 patients. The mean improvement in Hb was 2.45 g/dL (SD = 1.94) within 28 days of FCM administration, with the mean time taken to peak Hb levels being 6.3 days (SD = 8.63), which is earlier than expected, but was observed in this study and hence reported. The incidence of hypophosphataemia <0.8 mmol/L was 22.7% (n = 186), and <0.4 mmol/L was 1.6% (n = 9). This figure is lower than the numbers reported in previously published meta-analyses given that routine checks of serum phosphate levels were not conducted initially and hence could possibly be higher. The odds of developing hypophosphataemia (<0.8 mmol/L) were 27.7 (CI: 17.3-44.2, p < 0.0001) if baseline serum phosphate was less than 1 mmol/L. The odds of developing hypophosphataemia (<0.8 mmol/L) were 1.3 (CI: 1.08-1.59, p < 0.01) if the change in Hb levels observed after FCM administration were more than 4 g/dL. Hypophosphataemia after FCM administration is significant and FCM should be used by clinicians with caution.

Interaction between ferric carboxymaltose and denosumab causing severe hypocalcaemia and hypophosphataemia in a patient without chronic kidney disease.

Coadministration of ferric carboxymaltose and denosumab may cause hypocalcaemia and hypophosphataemia; however, this interaction is not well-described in the literature and has typically been described in patients with chronic kidney disease (CKD). We present a case of this interaction in a patient without preexisting CKD. We suggest the use of alternative iron preparations and an interval of at least 4 weeks between administrations.

Hypophosphataemia definitions, incidence and associated outcomes in paediatric intensive care: A retrospective cohort study in post-cardiac surgical patients <2 years of age.

AIM: Hypophosphataemia has been linked to higher morbidity and mortality in intensive care but there is inconsistency in the definition of hypophosphataemia for infants and children. We aimed to determine the incidence of hypophosphataemia in a group of at-risk children in paediatric intensive care unit (PICU) and associations with patient characteristics and clinical outcomes using three different hypophosphataemia thresholds. METHODS: Retrospective cohort study of 205 post-cardiac surgical patients <2 years of age admitted to Starship Child Health PICU, Auckland, New Zealand. Patient demographics and routine daily biochemistry for 14 days after PICU admission were collected. Rates of sepsis, mortality and length of mechanical ventilation were compared between groups with different serum phosphate concentrations. RESULTS: Out of 205 children, 6 (3%), 50 (24%) and 159 (78%) had hypophosphataemia at thresholds of <0.7, <1.0 and <1.4 mmol/L, respectively. There were no differences in gestational age at birth, sex, ethnicity or mortality in those with and without hypophosphataemia at any threshold. Children with a serum phosphate <1.4 mmol/L had more mean (SD) total hours of mechanical ventilation (85.2 (79.6) vs. 54.9 (36.2) h, P = 0.02) and those with mean serum phosphate <1.0 mmol/L had more mean hours of mechanical ventilation (119.4 (102.8) vs. 65.2 (54.8) h, P < 0.0001), episodes of sepsis (14% vs. 5%, P = 0.03) and longer length of stay (6.4 (4.8-20.7) vs. 4.9 (3.9-6.8) days, P = 0.02). CONCLUSIONS: Hypophosphataemia is common in this PICU cohort and serum phosphate <1.0 mmol/L is associated with increased morbidity and length of stay.

Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: Results from the Australian and the New Zealand Paediatric Surveillance Units survey.

BACKGROUND: X-linked hypophosphataemia (XLH) is the most common heritable form of rickets. Prevalence data varies across the literature between 1 in 20,000 and 1 in 200,000 per population. METHODS: Australian and New Zealand Paediatric Surveillance Units collected cross-sectional data from paediatricians on existing cases to estimate prevalence and characteristics of paediatric XLH in Australia and New Zealand. RESULTS: Seventy-five cases in Australia and 18 cases in New Zealand were identified. Estimated minimum prevalence based on these cases was 1.33 (1.04-1.66) per 100,000 and 1.60 per 100,000 (95%CI 0.97-2.58) in Australia and New Zealand respectively, with actual prevalence likely higher due to incomplete ascertainment. Despite a family history in most cases, delayed diagnosis was common, with 49 % diagnosed after 2 years of age. Delayed diagnosis was more common in sporadic versus familial cases. Most common clinical characteristics included leg bowing (89 %), bone and joint pain (68 %), abnormal gait (57 %) and short stature (49 %). There was a significant burden of orthopaedic disease and surgeries and a high rate of complications of nephrocalcinosis and hyperparathyroidism (32 % and 20 % respectively). Additionally, while guidelines stress the importance of multidisciplinary care, many did not have access to recommended health professionals, with only 3 % seeing a psychologist and 68 % seeing a dentist. This is despite the high psychological burden of XLH and a significant proportion (41 %) of this cohort having dental issues (tooth abscess, dental capping, tooth extraction). There were two cases from NZ without data available. Of the 91 cases with data collected, 46 % were on burosumab therapy. Consistent with clinical trials, those on burosumab had a higher serum phosphate levels (p < 0.001) at most recent follow-up. Three cases reported cancellation of orthopaedic surgery due to improvement in lower limb deformity after commencement of burosumab. CONCLUSION: These data describe the multisystem burden of disease for children with XLH with care impacted by delayed diagnosis and a lack of access to many health professionals, especially psychological support.

[Multiple bone fractures caused by severe hypophosphatemia in the course of the mandible tumour].

Not required for Clinical Vignette.

Severe hypophosphataemia can be an early sign of osteopetrorickets: a case report.

Osteopetrorickets is a rare complication of autosomal recessive ("malignant") osteopetrosis. Its prompt diagnosis is essential, because early suspicion of infantile osteopetrosis enables treatment with human stem cell transplantation, depending on the gene involved. It is important to identify not only the characteristic radiological changes of rickets, but also the coexistence of increased bone density, so as not to miss this very rare entity. Herein, a brief case report is presented.

Relationship of blood thiamine pyrophosphate to plasma phosphate and the response to enteral nutrition plus co-administration of intravenous thiamine during critical illness.

BACKGROUND: Hypovitamin B1 occurs frequently during critical illness but is challenging to predict or rapidly diagnose. The aim of this study was to evaluate whether plasma phosphate concentrations predict hypovitamin B1, enteral nutrition prevents hypovitamin B1 and intravenous thiamine supplementation achieves supraphysiological concentrations in critically ill patients. METHODS: Thirty-two enterally fed critically ill patients, with a plasma phosphate concentration ≤0.65 mmol/L, formed a nested cohort within a larger randomised clinical trial. Patients were assigned to receive intravenous thiamine (200 mg) twice daily, and controls were not administered intravenous thiamine. Thiamine pyrophosphate concentrations were measured at four time points (pre- and post-infusion and 4- and 6-h post-infusion) on days 1 and 3 in those allocated to thiamine and once in the control group. RESULTS: Baseline thiamine pyrophosphate concentrations were similar (intervention 88 [67, 93] vs. control 89 [62, 110] nmol/L, p = 0.49). Eight (25%) patients had hypovitamin B1 (intervention 3 vs. control 5), with two patients in the control group remaining insufficient at day 3. There was no association between baseline phosphate and thiamine pyrophosphate concentrations. Intravenous thiamine achieved supraphysiological concentrations 6 h post first infusion, with concentrations increasing to day 3. In the control group, thiamine pyrophosphate concentrations were not statistically different between baseline and day 3 (mean change: 8.6 [-6.0, 23.1] nmol/L, p = 0.25). CONCLUSIONS: Phosphate concentrations did not predict hypovitamin B1, which was observed in 25% of the participants. Enteral nutrition alone prevented the development of new hypovitamin B1. Administration of a single 200-mg dose of intravenous thiamine achieved supraphysiological concentrations of thiamine pyrophosphate, with repeated dosing sustaining this effect.

Osteomalacia hipofosfatémica ligada al cromosoma X (XLH): análisis de 5 pacientes adultos / X-linked hypophosphatemic osteomalacia (XLH): Study of 5 adult patients

Antecedentes: La osteomalacia hipofosfatémica ligada al cromosoma X (XLH) es un trastorno hereditario que puede ocasionar comorbilidades musculoesqueléticas altamente incapacitantes en edad adulta.ObjetivoAnalizar las características clínico-radiológicas, comorbilidades y complicaciones asociadas a la enfermedad y al tratamiento en la población adulta con XLH.MétodoEstudio retrospectivo de pacientes atendidos por XLH en un servicio de reumatología los últimos 10 años, evaluando los hallazgos clínico-radiológicos, las comorbilidades y las complicaciones asociadas.ResultadosSe incluyeron 5 pacientes de entre 39 y 75 años de edad. Todos presentaban talla baja, síntomas osteoarticulares y entesopatía radiológica. En 4 se observó artropatía degenerativa precoz de rodillas y caderas, y alteraciones dentales asociadas a su enfermedad. Todos los pacientes mayores de 50 años requirieron algún tipo de sustitución protésica. Dos pacientes presentaron fracturas de estrés en fémur, uno litiasis renal y otro desarrolló un hiperparatiroidismo terciario.ConclusionesLas manifestaciones musculoesqueléticas son frecuentes e invalidantes en la población adulta con XLH, por lo que un adecuado diagnóstico y manejo desde la infancia son esenciales para prevenir el desarrollo de complicaciones en la edad adulta asociadas a esta enfermedad. (AU)

Background: X-linked hypophosphatemic osteomalacia (XLH) is an inherited disorder that can cause highly disabling musculoskeletal comorbidities in adulthood.ObjectiveTo analyze the clinical-radiological characteristics, comorbidities and complications associated with the disease and treatment in an adult population with XLH.MethodRetrospective study of patients treated for XLH in a rheumatology department in the last 10 years, evaluating the clinical-radiological findings, comorbidities and associated complications.ResultsFive patients between 39 and 75 years of age were included. All had short stature, osteoarticular symptoms and radiological enthesopathy. Four patients had early degenerative arthropathy of the knees and hips, and dental alterations associated with their disease. All patients older than 50 years required some type of prosthetic replacement. Two patients had femoral stress fractures, one had renal lithiasis and another developed tertiary hyperparathyroidism.ConclusionsMusculoskeletal manifestations are frequent and disabling in the adult population with XLH, so proper diagnosis and management from childhood are essential to prevent the development of complications in adulthood associated with this disease. (AU)

Hypophosphataemia risk associated with ferric carboxymaltose in heart failure: A pooled analysis of clinical trials.

AIMS: Iron deficiency is a common finding among patients with heart failure (HF) and is associated with adverse outcomes, including decreased quality of life, increased risk of hospitalization, and decreased survival. Intravenous ferric carboxymaltose (FCM) has been shown to improve outcomes among patients with HF and concomitant iron deficiency, but FCM is associated with an increased risk of hypophosphataemia. We aimed to better characterize this risk among HF populations. METHODS AND RESULTS: This pooled analysis examined data from 41 studies of adults with iron deficiency across disease states and therapeutic areas. Among the 7931 patients treated with FCM available for analysis, 14% made up the HF subgroup. Additional subgroups included women's health (36%), non-dialysis-dependent chronic kidney disease (NDD-CKD; 27%), haemodialysis-dependent chronic kidney disease (HD-CKD; 1%), gastrointestinal (10%), neurology (3%), and other (10%). The incidence of post-baseline moderate or severe hypophosphataemia (i.e. serum phosphate [PO4 3- ] level <2.0 mg/dL) varied across the therapeutic areas, with the lowest incidences observed in the HD-CKD (0%), HF (8.1%), and NDD-CKD (12.8%) subgroups. The prevalence of moderate or severe hypophosphataemia among the women's health, other, gastrointestinal, and neurology subgroups was 30.1%, 40.6%, 51.0%, and 55.6%, respectively. In the HF subgroup, one patient (<0.1%) had a serum PO4 3- of <1.0 mg/dL recorded, compared with 4.8% and 4.0% of the subjects in the neurology and gastrointestinal groups, respectively. With the exception of the HD-CKD subgroup, mean serum PO4 3- levels decreased through weeks 2 to 4, and then returned toward baseline and plateaued by week 8. The strongest predictor of hypophosphataemia was preserved kidney function (estimated glomerular filtration rate: >60 mL/min/1.73 m2 vs. <30 mL/min/1.73 m2 ; odds ratio: 12.2). Among patients in the HF subgroup, the incidence of treatment-emergent adverse events potentially related to hypophosphataemia (e.g. cardiac failure, ventricular tachyarrhythmias, fatigue, muscle weakness, bone pain, neurological symptoms, and muscle pain) was lower among FCM-treated patients than among those receiving placebo, and lower among patients with a post-baseline PO4 3- <2 mg/dL vs. those not meeting such criteria. CONCLUSIONS: The risk of laboratory-assessed hypophosphataemia in HF patients treated with FCM was lower than that seen in patients in other therapeutic areas treated with FCM, and clinical events associated with hypophosphataemia are uncommon with FCM therapy in this population. Appropriate monitoring, particularly soon after administration in the unlikely event of repeated dosing in HF patients, will allow for further refinement of management strategies. [Correction added on 24 February 2023, after first online publication: In the preceding sentence, "…administration, will allow…" has been corrected to "…administration in the unlikely event of repeated dosing in HF patients, will allow…" in this version.].

Patient-reported outcomes measures of X-linked hypophosphataemia participants: findings from a prospective cohort study in the UK.

BACKGROUND: X-linked hypophosphataemia (XLH) is a rare genetic condition passed on through the X chromosome which causes multiple symptoms including weakened teeth, bones, and muscles. Due to the rarity of the condition, little is known about the health outcomes as reported by people with the disease. The objectives of this study were threefold: to characterise key patient reported outcome measures (PROMs) in adults with XLH, to identify clusters of symptom-severity groups based on PROMs, and to analyse the longitudinal progression of available PROMs. METHODS: Data from 48 participants from the Rare and Undiagnosed Diseases cohort Study (RUDY) was used to analyse both cross-sectional and longitudinal patient-reported outcomes. We analysed data for health-related quality of life (HRQL): EuroQol 5 dimensions-5 levels (EQ-5D-5L), Short-form 36 (SF-36) Physical Component Score (PCS), and SF-36 Mental Component Score (MCS), sleep: Pittsburgh sleep quality index (PSQI) and Epworth Sleepiness scale (ESS), fatigue: Fatigue Severity Scale (FSS) and Functional assessment of chronic illness therapy-fatigue (FACIT-F), pain: Short form McGill pain questionnaire version 2 (SF-MPQ-2) and PainDETECT, and mental well-being: Hospital anxiety and depression scale (HADS) anxiety and depression. Summary statistics, tests of mean differences, mixed-effects models, and cluster analysis were used to describe and examine the various health dimensions of individuals with XLH. RESULTS: Overall mean scores were EQ-5D-5L = 0.65, SF-36-PCS = 32.7, and SF-36-MCS = 48.4 for HRQL, ESS = 5.9 and PSQI = 8.9 for sleep, FSS = 32.8 and FACIT-F = 104.4 for fatigue, SF-MPQ-2 = 1.9 for pain, and HADS-depression = 4.7 and HADS-anxiety = 6.2 for mental well-being. 7% reported neuropathic pain (PainDETECT). Whilst many adults with XLH reported good outcomes, extreme or severe problems were reported across all outcomes. Cluster analysis identified that adults with XLH could be divided into two distinct groups, one reporting worse (35.3%) and the other better outcomes (64.7%) (less pain, fatigue, depression, and higher levels of sleep). Longitudinal analysis showed that FACIT-F and HADS-anxiety scores worsened slightly over two years with statistically significant (p < 0.05) time coefficients (b = - 2.135 and b = 0.314, respectively). CONCLUSION: Although about two thirds of adult participants of the RUDY cohort with XLH report good health outcomes, for a considerable third much worse outcomes are reported. More research is needed to examine why some experience good and others poor health outcomes and the characteristics which identify them.

Self-Administration of Burosumab in Children and Adults with X-Linked Hypophosphataemia in Two Open-Label, Single-Arm Clinical Studies.

INTRODUCTION: X-linked hypophosphataemia (XLH) is a rare, genetic renal phosphate-wasting disease, resulting from excess fibroblast growth factor 23 (FGF23) activity, which has a progressive and profound impact on patients throughout life. The monoclonal anti-FGF23 antibody, burosumab, is a subcutaneous injection indicated for the treatment of XLH in children and adults. Originally, burosumab was approved to be administered by a healthcare professional (HCP), but the option of self-administration would enable patient independence and easier access to treatment. Two open-label, single-arm clinical trials, conducted in Japan and Korea, have assessed the safety and efficacy of self-administration of burosumab in both children and adults with XLH. METHODS: In KRN23-003 (n = 15 children aged 1-12 years) and KRN23-004 (n = 5 children aged 3-13 years, n = 4 adults aged 21-65 years), children initially received 0.8 mg/kg of burosumab every 2 weeks and adults initially received 1.0 mg/kg of burosumab every 4 weeks. Self-administration was permitted from Week 4, and patients or carers were provided with training to inject correctly. RESULTS: In both trials, burosumab had an acceptable safety profile with mainly mild-to-moderate adverse events. Following self-administration, no patients reported serious treatment-emergent adverse events ≥ grade 3, injection-site reactions or hypersensitivity reactions related to burosumab. Serum phosphate and active vitamin D levels increased from baseline in children and adults. CONCLUSIONS: These results indicated that the efficacy and safety of burosumab when administered either by a carer or patient are similar to that when administered by an HCP and show that self-administration is a viable option for patients with XLH. TRIAL REGISTRATION NUMBERS: NCT03233126 and NCT04308096.