Judith Bubbear’s research while affiliated with Royal National Orthopaedic Hospital NHS Trust and other places

Hypophosphatasia (HPP) is a rare disease caused by deficient tissue–non-specific alkaline phosphatase (ALP) activity. Asfotase alfa is a tissue–non-specific ALP enzyme-replacement therapy which was reimbursed in the UK under a Managed Access Agreement (MAA). This analysis assessed safety and effectiveness of asfotase alfa in adults with HPP. This prospective, observational data collection included adults with paediatric-onset HPP enroled in the MAA and treated with asfotase alfa for ≥ 6 months to 5 years. Assessments included mobility, pain, and health-related quality of life (HRQoL), each reported at regular intervals through year 3. Analgesic use, fractures, and events of interest (EOIs) were each reported continuously throughout follow-up. Of 28 enroled treated adults, 24 were assessed for effectiveness. Distance walked in the 6-Minute Walk Test was median (min, max) 172.5 m (0.0, 380.0; n = 24) at baseline and improved by 157.3 m (− 171.0, 479.5; n = 16) at month 6; results were sustained throughout follow-up. Median (min, max) Bleck score was 6.0 (2.0, 9.0; n = 24) at baseline and increased to 6.5 (5.0, 9.0; n = 10) at month 36. Median (min, max) aggregate Brief Pain Inventory Short Form severity score was 8.0 (4.3, 10.0; n = 24) at baseline and improved to 4.4 (1.0, 7.8; n = 10) at month 36. During follow-up, 8 participants (33.3%) decreased or discontinued opioid use throughout follow-up and 4 (16.7%) reported fractures. Median (min, max) EQ-5D-3L utility scores improved from 0.21 (− 0.26, 0.60; n = 24) at baseline by 0.15 (− 0.36, 0.91; n = 24) at month 6 and were similar throughout follow-up. Injection site reactions were the most common treatment-related EOI, reported in 17 participants (60.7%). Three participants reported treatment-related serious adverse events. Asfotase alfa treatment improved mobility, physical function, pain, and HRQoL and was well tolerated. These data show the benefit of asfotase alfa in adults with paediatric-onset HPP.

Background: There is considerable practice variation in labelling, diagnosis and treatment of adults with sterile bone inflammation. We developed a expert consensus recommendations on the disease definition, diagnosis and treatment of this rare condition. Methods: Systematic literature review and Grading of Recommendations, Assessment, Development and Evaluations-based appraisal of evidence, two Delphi surveys and three digital and in-person consensus meetings with a multidisciplinary expert panel and patient representatives. Results: A consensus disease definition was developed and the term 'chronic non-bacterial osteitis' (CNO) is proposed to describe adults with sterile bone inflammation. For initial imaging evaluation of adults with suspected CNO, the panel recommends MRI or otherwise CT combined with nuclear imaging. Whole-body imaging at initial evaluation can be considered for diagnostic and prognostic purposes. Suggested first-line treatment in adults with active CNO includes non-steroidal anti-inflammatory drugs/cyclooxygenase 2-inhibitors. Second-line treatment preferably consists of intravenous bisphosphonates, and otherwise tumour necrosis factor-α inhibitors. Choice between them should be individualised, considering the presence of additional inflammatory features. The panel further discusses outcome measures, follow-up and management of adverse events and complications. Conclusions and future perspectives: These expert consensus recommendations are intended to support healthcare professionals worldwide in their care for adults with CNO. They also lay the groundwork for establishing international patient registries, translational research lines and multicentre trials, all of which are urgently required.

We assessed multiple components of muscle function in ten adults with X-linked hypophosphatemia (XLH) receiving burosumab treatment. Lower limb power (+ 9%), short physical performance battery (SPPB) score (+ 1.2 points), and physical activity (+ 65%) increased following 6 months of treatment, and hand grip increased (+ 10%) between 6 and 12 months of treatment. X-linked hypophosphatemia (XLH) is a rare genetic disorder of phosphate metabolism. Burosumab is a monoclonal antibody treatment shown to improve phosphate homeostasis and improve symptoms as well as fracture healing when used as a therapy for XLH in adults. However, little is known about its effects on the large deficits in multiple components of physical function previously reported in XLH. Ten adults (6 females, age 41.1 ± 15.7 y) were recruited from specialist centres in London and Bristol. During clinical visits for initial burosumab treatment and at 6-month and 12-month follow-up, physical function, and physical activity (PA) assessments were performed. In detail, lower limb power was assessed by mechanography via a countermovement jump, mobility by short physical performance battery (SPPB), functional capacity by 6-min walk test (6MWT), upper limb strength by hand grip dynamometry, and PA via an International Physical Activity Questionnaire (IPAQ). Differences between baseline and 6-month follow-up, and in a subset of 5 patients between 6- and 12-month follow-up, were assessed. Lower limb power increased by 9% (P = 0.049) from baseline to 6 months, as did SPPB score (+ 1.2 points, P = 0.033) and total PA (+ 65%, P = 0.046) although hand grip and 6MWT did not differ. Only for hand grip was a significant improvement (+ 10%, P = 0.023) seen between 6 and 12 months. Burosumab treatment is associated with improved lower limb function and mobility at 6 months, with improvement in hand grip strength at 12 months. Future studies should explore the underlying mechanisms and describe on function and other patient outcomes.

Background Adults with sterile bone inflammation are variably labelled as Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO)-syndrome, chronic nonbacterial osteomyelitis, chronic recurrent multifocal osteomyelitis (CRMO), pustulotic arthro-osteitis, or sternocostoclavicular hyperostosis. A standardized diagnostic approach for this rare disease is lacking, and clinical management is challenging due to limited available evidence. Objectives • 1) To define overarching principles for disease definition, terminology, and clinical care of adults with sterile bone inflammation; • 2) To develop points to consider (PtCs) for diagnosis and management, integrating existing evidence and multidisciplinary expert opinion. Methods Our consensus initiative comprised a systematic literature review and appraisal of evidence, two Delphi surveys, a digital and a two-day in-person consensus meeting with an international multidisciplinary expert panel and patient representatives. Results Three overarching principles concerning disease definition, terminology, and organization of care were defined, as well as 20 PtCs regarding diagnosis and management. Panel members and patient representatives agreed to uniformly use the diagnostic term “chronic nonbacterial osteitis (CNO)” for adults. For the initial evaluation of suspected adult CNO patients, the PtCs highlight the limited value of laboratory investigations and bone biopsies against the crucial role of imaging, which is preferably done by magnetic resonance imaging, or otherwise by computed tomography combined with nuclear imaging/bone scintigraphy. Whole-body imaging can be validly considered during initial evaluation, also in patients with clinically localized disease. Management outcomes emphasize patient-reported indices like pain since the prognostic value of persistent radiologic activity is yet unknown. A suggested treatment algorithm for adults with symptomatic CNO includes the initial use of non-steroidal anti-inflammatory drugs/cyclooxygenase 2-inhibitors in most patients, whereafter bisphosphonates or tumor necrosis factor alpha inhibitors can be considered. Typically, bisphosphonates are preferred as first-choice, though choice depends on individual patient factors and the presence of additional inflammatory features. Final PtCs concern follow-up, management of adverse events and complications, and also cover a research agenda. Conclusion These first internal and multidisciplinary overarching principles and PtCs offer clinical guidance on the terminology, diagnosis, and management of adults with sterile bone inflammation, i.e. CNO. This consensus initiative will contribute to the timely recognition of adult CNO, improve clinical care, and facilitate future systematic and collaborative research. REFERENCES NIL Acknowledgements The authors extend special thanks to physicians completing the Delphi surveys, and to the patient representatives of the Dutch CNO patient association for their contribution to this work. Disclosure of Interests Elizabeth Winter Speaker at Amgen and UCB, Advisory board of Amgen and UCB, Olaf Dekkers: None declared, Caroline Marie Andreasen: None declared, Natasha Appelman-Dijkstra: None declared, Simone Appenzeller: None declared, Gunter Assmann: None declared, Judith Bubbear: None declared, Oana Bulaicon: None declared, Roland Chapurlat: None declared, Varvara Choida: None declared, Gavin Clunie: None declared, Salvatore D’Angelo: None declared, Dimitrios Daoussis Speaking fees from UCB, Pfizer, Novartis, BMS, MSD, Janssen, Αbbvie, Lilly and Aenorasis.Honoraria for participation in advisory boards from UCB, Pfizer, Novartis, BMS, MSD, Janssen, Αbbvie, Lilly and Aenorasis. Torsten Diekhoff Speaker for Canon MS, Novartis, MSD, UCB and Roche; Advisory board: Lilly; Grant/Support: Canon MS, ASAS, Marcel Flendrie: None declared, Olivier Fogel: None declared, Roba Ghossan: None declared, Hermann Girschick: None declared, Femke van Haalen: None declared, Neveen Hamdy: None declared, Barbara Hauser grants, personal fees and other from UCB, Kyowa Kirin, Eli Lilly, Amgen, Thornton & Ross and Gedeon-Richter and Fresenius Kabi outside the submitted work;., Christian Hedrich: None declared, Philip S Helliwell: None declared, Kay-Geert Hermann Consulting fees from AbbVie, lecture fees from MSD, Novartis, Pfizer. Co-founder of BerlinFlame GmbH. Antonella Insalaco: None declared, Anne Grethe Jurik: None declared, Mitsumasa Kishimoto received consulting fees and/or honoraria from AbbVie, Amgen, Asahi-Kasei Pharma, Ayumi Pharma, BMS, Chugai, Daiichi Sankyo, Eisai, Gilead, Janssen, Lilly, Novartis, Pfizer, Tanabe-Mitsubishi, and UCB. WIllem Lems speaking fees of Amgen, UCB, Pfuzer, Galapagos., member of advisory boards of Amgen, UCB, Pfuzer, Galapagos. Paivi Miettunen: None declared, Burkhard Muche: None declared, Ana Navas Cañete: None declared, Natalia Palmou-Fontana: None declared, Frits Smit: None declared, James Teh: None declared, Charlotte Verroken: None declared, Kurt de Vlam: None declared, Daniel Wendling speaking fees of AbbVie, BMS, MSD, Pfizer, Nordic Pharma, UCB, Novartis, Lilly, Janssen, Galapagos, Celltrion. member of advisory board of AbbVie, BMS, MSD, Pfizer, Nordic Pharma, UCB, Novartis, Lilly, Janssen, Galapagos, Celltrion., Wei Zhou: None declared, Hans-Georg Zmierczak: None declared, Anne Leerling: None declared.

https://asbmr.onlinelibrary.wiley.com/doi/epdf/10.1002/jbm4.10815

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666.

Paget disease of bone is a metabolic disorder with a strong genetic component, characterised by pronounced disorganised bone remodelling. Complications of this disease include an increased risk of developing bone neoplasms. Here, we describe the case of a 60-year-old Italian patient with Paget disease of bone, presenting with an osteoclast-rich tumour. Our analysis of this entity, based on the clinical, morphological and genetic data (whole exome sequencing), suggests that osteoclast-rich lesions in Paget disease of bone are genetically distinct from classical giant cell tumour of bone. We discuss the importance of differentiating these osteoclast-rich lesions.