Browsing by Author "Imel, Erik Allen"

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    12589 Two Systematic Reviews Of Treatment Efficacy On Patient Important Outcomes In Adult X-linked Hypophosphatemia
    (Oxford University Press, 2024-10-05) Ali, Dalal S.; Mirza, Reza; Alsarraf, Farah; Hussein, Salma; Appelman-Dijkstra, Natasha; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Brandi, Maria Luisa; Chaussain, Catherine; Cohen-Solal, Martine; Crowley, Rachel K.; Dandurand, Karel; Florenzano, Pablo F.; Fukumoto, Seiji; Gagnon, Claudia; Goodyer, Paul; Grasemann, Corinna; Imel, Erik Allen; De Beur, Suzanne Marie Jan; Lewiecki, E. Michael; Morgante, Emmett; Ward, Leanne; Aziz Khan, Aliya; Guyatt, Gordon; Medicine, School of Medicine
    Objective: Our objective was to examine the highest certainty evidence addressing the management of X-linked hypophosphatemia in adults, aiming to inform treatment recommendations. Eligibility criteria: We searched Embase, MEDLINE, Web of Science, and Cochrane from inception to March 2023 and included RCTs and observational studies enrolling individuals ≥ 18 years diagnosed with XLH on clinical grounds or with a confirmed pathogenic variant in PHEX. Manuscripts evaluating the effectiveness of burosumab compared to either no treatment or conventional therapy (phosphate salts and active vitamin D) or evaluating conventional therapy compared to no treatment were selected. Methods: Two reviewers independently determined eligibility, conducted data extraction, and assessed the risk of bias (RoB). GRADE was used to assess certainty of evidence. Results: After removing duplicates from 7,043 citations, we assessed 254 full texts. Of those, one RCT proved eligible. The RCT of burosumab versus no treatment was at low RoB with certainty of evidence on individual outcomes ranging from high to very low. Burosumab probably improves pain inferred from fracture and pseudofracture healing (moderate certainty); however, burosumab probably has little or no impact on direct pain measures (moderate certainty). While burosumab may reduce the need for parathyroidectomy, indicated by lowered PTH levels (low certainty), it has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may also increase dental abscesses (low certainty). No formal comparisons of burosumab and conventional therapy exist; therefore, our low certainty evidence inferences regarding burosumab versus conventional therapy were based on indirect evidence from comparisons of burosumab versus no treatment and from conventional therapy versus no treatment. Observational studies proved at high RoB providing very low certainty of evidence regarding the impact of conventional therapy versus no treatment. This evidence pertained to the reduction in the risk of parathyroidectomy, as well as the reduction in the burden of symptoms caused by chronic hypophosphatemia. Conclusion: Burosumab when compared to no treatment may improve pain through fracture healing and may reduce the need for parathyroidectomy, but it could also increase the risk of dental abscess. However, when using direct measures of pain and function, burosumab demonstrated probably little or no impact on pain and stiffness, little or no impact on fatigue, and may have had little to no impact on mobility. Very low certainty exists regarding conventional therapy versus no treatment in adults. Overall, our review highlights the need for more data to better understand the long-term impact of burosumab and conventional therapy on patient-important outcomes.
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    9295 Characteristics Of Adults with Autosomal Dominant Hypocalcemia Type 1 (ADH1) Enrolled In The CLARIFY Disease Monitoring Study
    (Oxford University Press, 2024-10-05) Wai Ing, Steven; Harmatz, Paul; Mora, Stefano; Imel, Erik Allen; Tebben, Peter J.; Lowe Warren, Mark; Ma, Nina; Aziz Khan, Aliya; Palermo, Andrea; Decallonne, Brigitte; Lemoine, Sandrine; Mantovani, Giovanna; Linglart, Agnes; Wasserman, Halley; Barbosa, Ana Paula; Cardot-Bauters, Catherine; Scott Roberts, Mary; Mathew, Arun; Adler, Scott; Zillikens, Maria Carola; Clifton-Bligh, Roderick John; Rejnmark, Lars; Medicine, School of Medicine
    Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) concentrations, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. While a rare disease, ADH1 is one of the more frequently identified causes of genetic hypoparathyroidism. Conventional therapy includes calcium (Ca) and/or active vitamin D, but this regimen incompletely corrects the hypocalcemia and is associated with persistent hypercalciuria, which may result in renal complications including nephrocalcinosis (NC), nephrolithiasis (NL), and chronic kidney disease (CKD). The CLARIFY disease monitoring study [NCT05227287] is a global, multicenter, longitudinal study to understand disease burden, management, and progression in children and adults with ADH1 over a 5-year period. Here we report data on the characteristics of adult participants at study entry. As of November 2023, 45 adults (≥18 years) with ADH1 were enrolled, with a mean±SD age of 42.1±16.5 years (range 18-80). The mean±SD age of a hypocalcemia diagnosis was 19.1±19.1 years, while the mean±SD age for a diagnosis of ADH1 was 28.2±20.6 years. As reported on medical history, in decreasing order of prevalence, 36% (16) had NC, 22% (10) had intracranial calcifications, 11% (5) had history of seizures, 11% (5) had CKD, 9% (4) had cataracts, 7% (3) had NL, and 4% (2) had undergone renal transplant. Treatment data were available for 43 participants and included the following: 74% (32) Ca and active vitamin D, 9% (4) Ca alone, 9% (4) active vitamin D alone, 37% (16) magnesium, 33% (14) thiazide diuretics, 26% (11) potassium, 7% (3) phosphate binder, 7% (3) PTH, and 5% (2) no treatment. Mean±SD fasting values collected prior to conventional therapy dose are presented. PTH concentrations (10.1±8.2 pg/mL [nl 15-65]) and albumin-corrected calcium ([cCa]=7.5±1.0 mg/dL [nl 8.5-10.5]) were low. Despite the low mean cCa, the mean 24-hr urine calcium was elevated (268±183 mg/d, [nl <250 women, <300 men]). Blood phosphate was 4.8±0.8 mg/dL [nl 2.5-4.8] while blood magnesium was 1.8±0.2 mg/dL [nl 1.8-2.4]. 25-OH vitamin D was 35.0±13.5 ng/mL [nl 30-80]. Renal function as assessed by CKD-EPIcr_R showed eGFR of 86±23 mL/min/1.73m² (range 36-123). This study represents the largest cohort of adults with ADH1 described to date. These data highlight variability in therapeutic approaches in a real-world setting with some participants receiving up to 6 different medications/supplements. Despite being followed in expert centers, and treated with available therapies, patients on average have low cCa with relatively high 24-hr urine calcium excretion. The CLARIFY study provides an opportunity to better understand the progression and burden of disease in participants with ADH1.
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    Burosumab Provides Sustained Improvement in Phosphorus Homeostasis and Heals Rickets in Children Aged 1 to 4 Years With X-Linked Hypophosphatemia (XLH)
    (Oxford University Press, 2021) Gottesman, Gary; Imel, Erik Allen; Carpenter, Thomas O.; Chen, Angel; Skrinar, Alison; Roberts, Mary Scott; Whyte, Michael P.; Medicine, School of Medicine
    XLH is the most common heritable rickets. Affected children have high levels of circulating FGF23 that cause hypophosphatemia with consequent rickets and lower limb deformity. Burosumab, a fully human monoclonal antibody that binds FGF23, is FDA-approved for the treatment of XLH in children ≥6 months old and adults. Herein, we report final, 3-year safety and efficacy data from an open-label, phase 2 study of burosumab in children 1 to <5 years old at baseline (NCT02750618). Eligibility required hypophosphatemia and radiographic evidence of rickets. The primary efficacy endpoint was change from baseline in fasting serum phosphorus (Pi). Secondary endpoints included Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C). Patients received burosumab subcutaneous Q2W starting at 0.8 mg/kg for 160 weeks (64-week treatment + 96-week treatment extension periods). All 13 enrolled patients completed the 64-week treatment period; 1 left the study to transition to commercially available burosumab, and 12 completed all 160 weeks. Baseline mean (SD) age was 2.9 (1.1) years; 69% were boys; all had previously received oral phosphate salts and active vitamin D. Burosumab rapidly corrected fasting serum Pi with mean (SD) levels of 2.5 (0.3) mg/dL at Baseline, 3.7 (0.5) mg/dL at Week 1 (W1), 3.4 (0.5) mg/dL at W64, and 3.4 (0.5) mg/dL at W160 (normal range: 3.2–6.1 mg/dL). Lower RSS indicated improved rickets. Total RSS decreased from 2.9 (1.4) at Baseline to 1.2 (0.5) at W40 and to 0.9 (0.5) at W64 and was maintained through W160 [1.0 (0.6)]. Positive RGI-C scores indicate healing rickets relative to Baseline. Global RGI-C scores indicating substantial healing (≥+2) at W40 [+2.2 (0.3)] and W64 [+2.2 (0.4)] were maintained through W160 [+2.2 (0.4)]. Similarly, lower limb deformity RGI-C scores were +1.2 (0.6) at W40 and +1.5 (0.5) at W64, and sustained healing was evident at W160 [+2.0 (0.3)]. Wrist and knee RSSs and RGI-C scores similarly improved. The upper limit of normal for serum ALP ranged from 297 to 345 U/L depending on the child’s age and sex. Mean ALP was 549 (194) U/L at Baseline, normalized by W40 [335 (88) U/L], and was sustained through W160 [302 (71) U/L]. The burosumab safety profile over 160 weeks resembled previous pediatric studies; no new safety concerns emerged. All patients had ≥1 treatment-emergent adverse event (TEAE). All TEAEs were mild (Grade 1) or moderate (Grade 2) except for one patient with a grade 3 TEAE (food allergy) and one with a grade 3 TEAE (increased serum amylase, 92% salivary/8% pancreatic). One patient had a serious TEAE (dental abscess leading to hospitalization). These grade 3 and serious TEAEs were considered unrelated to study drug. Burosumab rapidly restored Pi homeostasis, improved rickets, and normalized serum ALP in children with XLH aged 1 to <5 years with no new safety concerns. Improvements were maintained during the 3 years of treatment.
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    Congenital Conditions of Hypophosphatemia in Children
    (Springer, 2021) Imel, Erik Allen; Pediatrics, School of Medicine
    Great strides over the past few decades have increased our understanding of the pathophysiology of hypophosphatemic disorders. Phosphate is critically important to a variety of physiologic processes, including skeletal growth, development and mineralization, as well as DNA, RNA, phospholipids, and signaling pathways. Consequently, hypophosphatemic disorders have effects on multiple systems, and may cause a variety of nonspecific signs and symptoms. The acute effects of hypophosphatemia include neuromuscular symptoms and compromise. However, the dominant effects of chronic hypophosphatemia are the effects on musculoskeletal function including rickets, osteomalacia and impaired growth during childhood. While the most common causes of chronic hypophosphatemia in children are congenital, some acquired conditions also result in hypophosphatemia during childhood through a variety of mechanisms. Improved understanding of the pathophysiology of these congenital conditions has led to novel therapeutic approaches. This article will review the pathophysiologic causes of congenital hypophosphatemia, their clinical consequences and medical therapy.
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    Hypocalcemia in a 15 Year Old With New Onset Type 2 Diabetes Mellitus
    (Oxford University Press, 2021) Becerril Romero, Carlos C.; Schneider Aguirre, Rebecca; Imel, Erik Allen; DiMeglio, Linda A.; Gohil, Anisha; Pediatrics, School of Medicine
    Background: Diabetic ketoacidosis and significant hyperglycemia are associated with known electrolyte derangements in sodium, potassium, and phosphorus. Hypocalcemia and hypoparathyroidism occurring in uncontrolled diabetes are rare. We present a case of new-onset diabetes with severe hypocalcemia. Case: A 15-year-old obese Caucasian male with ADHD and autism presented to the Emergency room due to hyperglycemia found on laboratory evaluation for hypertension. Serum glucose was 563 mg/dL, serum bicarbonate 24 meq/L (21 - 31 meq/L), and HgbA1C 11.4% (4.0 - 5.6%). He was admitted to initiate insulin and for diabetes education. On admission, hypocalcemia was noted: serum calcium 6.6 mg/dL (8.5 - 10.5 mg/dL), alkaline phosphatase 352 units/L (48 - 277 units/L), and albumin 4.6 g/dL (3.5 - 5.0 g/dL). Repeat testing revealed serum calcium 5.1 mg/dL, phosphorus 4.3 mg/dL (2.5 - 4.5 mg/dL), and magnesium 1.7 mg/dL (1.6 - 2.9 mg/dL). He endorsed a 2 month history of tetany, paresthesia, and muscle weakness. Due to food aversions, his dietary intake of calcium and vitamin D was minimal. He had limited sun exposure. Subsequent PTH was 40 pg/mL (10 - 65 pg/mL) with concurrent serum calcium of 6.5 mg/dL. QTc was prolonged [529 msec (<440 msec)], prompting transfer to the intensive care unit for telemetry, intravenous calcium gluconate, and regular calcium monitoring. Treatment was commenced with cholecalciferol 2000 international units daily and oral calcium carbonate (50 mg elemental calcium/kg/day) in divided doses for presumed Vitamin D deficiency. After several intravenous calcium gluconate doses over 24 hours, the patient’s QTc and ionized calcium normalized. At discharge, calcium was 8.5 mg/dL. He was discharged on the above regimen of calcium and cholecalciferol, and basal and bolus insulin. After discharge, laboratory results returned indicating negative diabetes autoantibodies (GAD 65, Insulin, IA-2) and 25-OH Vitamin D <10 ng/mL (30 - 100ng/mL). Two days after discharge, calcium was 7.3 mg/dL. Two weeks later, labs were: 25-OH Vitamin D 11.3 ng/mL, PTH 10.4 pg/mL, and calcium 9.6 mg/dL. Conclusion: This teen presented with new-onset type 2 diabetes and symptomatic hypocalcemia, an atypical feature of new-onset diabetes. This patient’s hypocalcemia was likely due to both vitamin D deficiency and hypoparathyroidism. He had a low vitamin D level and poor calcium intake with elevated alkaline phosphatase; however, his high normal serum phosphorus and inappropriately normal PTH (instead of elevated in the setting of severe hypocalcemia) indicated a component of hypoparathyroidism. Calcium normalized with detectable 25-OH Vitamin D levels but PTH remained low. Our case highlights the importance of recognizing both that electrolyte abnormalities at diabetes onset may not be directly attributable to diabetes/hyperglycemia and that vitamin D deficiency and hypoparathyroidism may co-exist.