No abstract

Graves’ hyperthyroidism is characterised by the presence of autoantibodies that stimulate the thyroid stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. Conventional treatments including antithyroid medication, radioiodine or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy in the case of the latter two options. The demand for new therapeutic options combined with greater insight into basic immunobiology, has led to the emergence of novel approaches to treat Graves’ hyperthyroidism. The current therapies under investigation include biologics, small-molecules and peptide immunomodulation. There is a growing focus on TSHR-specific treatment modalities, which carry the advantage of eliciting a specific, targeted approach, with the aim of avoiding disruption of the functioning immune system. These therapies offer the new opportunity to supersede the inadequate treatments currently available for some Graves’ patients, with the hope of successful restoration of euthyroidism without the need for ongoing therapy. Several of these therapeutic options have the potential to translate into clinical practice in the near future. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves’ hyperthyroidism.

Having benign paroxysmal positional vertigo (BPPV) puts patients at a signifi cantly higher risk of falling. It is poorly recognised and diagnosis is frequently delayed. BPPV has been studied in outpatient settings, but there have been no studies looking at the prevalence in patients admitted with falls. This study aims to establish how common BPPV is in these patients. For a 4-month period, patients admitted on an unselected medical take were screened for an admission precipitated by a fall. Patients who consented were assessed for BPPV using the Dix-Hallpike manoeuvre. Patients who tested positive were treated using the Epley manoeuvre. The assessments were carried out by specialist physiotherapists who were experienced at assessing and diagnosing patients with peripheral vestibular disorders. Out of the 111 patients initially identifi ed, 37 (33%) were considered to be appropriate and consented to be part of the study. Of these, 20 patients (54%) had a positive Dix-Hallpike manoeuvre. Of the patients included in the study, over half tested positive for BPPV. This merits further study. Potentially, there is a proportion of patients admitted with falls who have an easily treatable contributing factor that is not being identifi ed with standard practice.

Summary Objective B lymphocyte activating factor (BAFF), a member of the tumour necrosis factor superfamily, is essential for B cell activation, differentiation and survival. Elevated circulating BAFF levels have been found in patients with several autoimmune conditions, including Graves’ disease. In addition, BAFF gene variants have been associated with Graves’ disease in a Taiwanese cohort, and with several other autoimmune conditions in non‐Taiwanese populations. Design and methods We performed a case‐control association study to investigate two BAFF polymorphisms (rs9514828 and rs4000607) in a UK cohort of 444 patients with Graves’ disease. Genotype frequencies were compared to those from 447 local controls and more than 5000 healthy controls from the Wellcome Trust case‐control consortium (WTCCC2). Results There was a significant difference in the frequency of the AA genotype at rs4000607 between the Graves’ disease cohort and both the local controls (P = 0.045) and the WTCCC2 controls (P = 4.56 × 10−6). Furthermore, the frequency of the A allele was found to be increased in the Graves’ disease group compared to WTCCC2 controls (P = 0.02, OR 1.20 (95% CI 1.03‐1.41). No association was observed at the rs9514828 locus. Conclusion Dysfunction of the humoral immune system is an obligatory pathophysiological component of Graves’ disease, hence BAFF is an excellent functional candidate gene. We have demonstrated, for the first time, a significant association of the BAFF polymorphism rs4000607 with Graves’ disease in a UK cohort. Further work to elucidate the role of BAFF in the pathogenesis of Graves’ disease is now warranted.

Graves’ disease is a rare disorder that continues to present clinicians and families with a series of challenges. There are no new established treatments for children or adolescents, but the outcomes of recent clinical trials and meta-analyses have helped clinicians to prepare families for the road ahead. We have a more refined understanding of how to administer antithyroid drugs, which one to use and how long to treat the young person. We also have a greater insight into how best to reduce any risks associated with surgery and radioiodine. We understand more about long-term outcomes and their determinants and have greater awareness about the impact of the disease and its treatment on quality of life. A holistic approach to management is key to supporting and counselling young people and their families about the diagnosis and management options. In this review, we will discuss the recent literature and reflect on how this should be translated into clinical practice.

Aromatase inhibitor therapy is associated with a positive height outcome in FMPP but the outcome with and without intervention is unpredictable. Clinicians need to be cautious when counselling families about the potential height outcome in FMPP.

Context The genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients. Objective We aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data. Design and Participants rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped. Results The C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10–9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (<30 years) (P allele=1.70 × 10–10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10–5) and age of onset (P allele=5.63 × 10–8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301. Conclusion The rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.

ObjectiveA suboptimal quality of life (QoL) has been reported in patients with Graves’ disease treated in adult life, but long‐term QoL in those treated in childhood and adolescence is unclear. We wanted to understand how Graves’ disease and its management impact on the physical, psychological and social well‐being of young people and their longer‐term QoL.Design, patients and measurementsTwo questionnaires were used to assess QoL and patient experience of Graves’ disease; PedsQL™ Generic Core Scales and a Graves’ disease questionnaire devised for this project. The anonymized questionnaires were sent to young people (<30 years) diagnosed with Graves’ disease in childhood and adolescence and managed at a tertiary paediatric endocrine unit in the North of England. Respondent QoL scores were compared with a healthy UK cohort.ResultsQuestionnaires were sent to 51 young people, and 26 responded (51%). Graves’ patients reported a lower total QoL score compared with the healthy cohort (p = .003). This was particularly apparent in the psychosocial domain (p = .0016). No patient regretted having definitive treatment (surgery/radioiodine), and all said they would recommend it to others. Half of those who had received definitive treatment still did not feel recovered. There was no difference in the long‐term QoL in those who did/did not receive definitive treatment (p = .40).ConclusionsThis study highlights short‐ and long‐term impacts on the QoL and general well‐being of young people with Graves’ disease. There were no regrets regarding the choice of definitive treatment. This information will help inform the counselling of patients and their families.