An updated systematic review and meta-analysis of randomised controlled trials on the effects of urate-lowering therapy initiation during a gout flare.

BACKGROUND: There is uncertainty about the optimal time to start urate-lowering therapy (ULT) in the setting of a gout flare. The aim was to perform a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the effects of ULT initiation during a gout flare. METHODS: This systematic review was conducted in accordance with PRISMA methodology. MEDLINE, EMBASE and The Cochrane Library were searched for studies published between database inception to 1 March 2023. RCTs published in English that examined ULT initiation during a gout flare in adults ≥18 years were included. The quality of included studies was assessed using the revised Cochrane Risk of Bias tool 2.0. Data were extracted for the following outcomes: patient-rated pain score, duration of gout flare, recurrent gout flares, time to achieve target serum urate, adherence to ULT, patient satisfaction with treatment and adverse events. Meta-analyses were performed using Review Manager v5.4. This study is registered on PROSPERO, number CRD42023404680. RESULTS: A total of 972 studies were identified and of these, six RCTs met the criteria for inclusion in the analysis. Three studies were assessed as having high risk of bias, one study as having some concerns, and two studies as having low risk of bias. In total, there were 445 pooled participants; 226 participants randomised to early initiation of ULT and 219 to placebo or delayed initiation of ULT. Allopurinol was used in three studies, febuxostat in two studies and probenecid in one study. Few participants (n = 62, 13.9 %) had tophaceous gout. Participants with renal impairment were excluded from most studies. There were no differences in patient-rated pain scores at baseline, days 3-4, days 7-8, day 10 or days 14-15 (p ≥ 0.42). Additionally, there was no significant difference in time to resolution of gout flare (standardised mean difference 0.77 days; 95 % CI -0.26 to 1.79; p = 0.14) or the risk of recurrent gout flare in the subsequent 28 to 30 days (RR 1.06; 95 % CI 0.59 to 1.92; p = 0.84). Adverse events were similar between groups. The included studies did not report time to achieve target serum urate, long-term adherence to ULT, or patient satisfaction with treatment. CONCLUSION: There appears to be no evidence for harm or for benefit to initiating ULT during a gout flare. These findings have limited applicability to patients with tophaceous gout, or those with renal impairment.

Gout and the COVID-19 pandemic.

PURPOSE OF REVIEW: This review gives an overview of recently published articles on COVID-19 and gout. RECENT FINDINGS: People with gout are likely to be at an increased risk of poor outcomes after COVID-19 infection due to comorbid cardiometabolic conditions. The effects of chronic hyperuricemia on trained immunity, and the hyperinflammatory state induced by gout itself may also play a role. Frequent courses of glucocorticoids for gout flares may be associated with adverse outcomes after COVID-19 infection and reduced immunogenicity to the COVID-19 vaccination. Similarities between the pathophysiology of gout flares and the dysregulated inflammatory response of severe COVID-19 have been identified. Medications used in the treatment of gout, including colchicine and interleukin-1 inhibitors, have shown promise in the treatment of COVID-19 in clinical trials. Overall, the COVID-19 pandemic has had a negative impact on gout care, with patients reporting more difficulty with disease control, accessing medications and healthcare, and poorer quality of life. SUMMARY: The COVID-19 pandemic has created many challenges for people with gout. At present, there is a lack of guidance on the management of gout during the pandemic and paucity of research assessing outcomes of COVID-19 infection in people with gout.

Genetic and Clinical Findings in an Ethnically Diverse Cohort with Retinitis Pigmentosa Associated with Pathogenic Variants in CERKL.

Autosomal recessive retinitis pigmentosa is caused by mutations in over 40 genes, one of which is the ceramide kinase-like gene (CERKL). We present a case series of six patients from six unrelated families diagnosed with inherited retinal dystrophies (IRD) and with two variants in CERKL recruited from a multi-ethnic British population. A retrospective review of clinical data in these patients was performed and included colour fundus photography, fundus autofluorescence (AF) imaging, spectral domain-optical coherence tomography (SD-OCT), visual fields and electroretinogram (ERG) assessment where available. Three female and three male patients were included. Age at onset ranged from 7 years old to 45 years, with three presenting in their 20s and two presenting in their 40s. All but one had central visual loss as one of their main presenting symptoms. Four patients had features of retinitis pigmentosa with significant variation in severity and extent of disease, and two patients had no pigment deposition with only macular involvement clinically. Seven variants in CERKL were identified, of which three are novel. The inherited retinopathies associated with the CERKL gene vary in age at presentation and in degree of severity, but generally are characterised by a central visual impairment early on.

Do Serum Urate-Associated Genetic Variants Differentially Contribute to Gout Risk According to Body Mass Index? Analysis of the UK Biobank.

OBJECTIVE: To examine whether urate-associated genetic variants differ in their influence on gout risk according to body mass index (BMI). METHODS: This research was conducted using the UK Biobank Resource (n = 358,728). Participants were divided into 3 groups: BMI <25 kg/m2 (low/normal), BMI ≥25 kg/m2 -<30 kg/m2 (overweight), and BMI ≥30 kg/m2 (obese). Gene-BMI interactions for gout association were tested by logistic regression using a urate genetic risk score (GRS). RESULTS: Compared to participants with a GRS less than the mean, the prevalence of gout was higher in those with a GRS greater than or equal to the mean in the low/normal BMI group (0.27% versus 0.77%), in the overweight BMI group (1.02% versus 3.02%), and in the obese BMI group (2.49% versus 6.23%). A GRS greater than or equal to the mean was positively associated with gout compared to a GRS less than the mean in the low/normal BMI group (odds ratio [OR] 2.89 [95% confidence interval (95% CI) 2.42-3.47]), in the overweight BMI group (OR 3.09 [95% CI 2.84-3.36]), and in the obese BMI group (OR 2.65 [95% CI 2.46-2.86]). There was a mildly attenuated effect of the GRS on gout risk in the obese BMI group compared to the overweight BMI group, but no difference in the effect of the GRS between the low/normal BMI and overweight BMI groups, nor between the low/normal BMI and obese BMI groups. CONCLUSION: The association of a urate GRS with gout is mildly attenuated in obese individuals compared to overweight individuals. However, genetic variants have a strong effect on gout risk in those with overweight and obese BMIs, with an effect similar to that observed in low/normal BMI.

Genetic advances in gout: potential applications in clinical practice.

PURPOSE OF REVIEW: Many novel genetic associations in the field of hyperuricaemia and gout have been described recently. This review discusses advances in gout genetics and their potential clinical applications. RECENT FINDINGS: Genome-wide association studies have identified approximately 30 serum urate-associated loci, some of which represent targets for drug development in gout. Some genes implicated in initiating the inflammatory response to deposited crystals in gout flares have also been described. In addition, genetic studies have been used to understand the link between hyperuricaemia and other comorbidities, particularly cardiometabolic diseases. ABCG2 has been established as a key genetic determinant in the onset of gout, and plays a role in the progression and severity of disease. Recent pharmacogenetic studies have also demonstrated the association between ABCG2 and poor response to allopurinol, and the link between HLA-B58:01 genotype and adverse drug reactions to allopurinol. SUMMARY: Advances in gout genetics have provided important molecular insights into disease pathogenesis, better characterized the pharmacogenetics of allopurinol, and raised the possibility of using genetic testing to provide personalized treatment for patients. Prospective studies are now needed to clarify whether genetic testing in gout provides further benefit when added to established clinical management.

Qualitative study: the experience and impact of living with Behcet's syndrome.

AIM: Behcet's syndrome is a rare chronic multisystemic vasculitis of unknown aetiology, is unpredictable and can cause life-threatening complications. This qualitative study aims to explore the experiences of patients living with Behcet's syndrome in New Zealand. METHODS: Eight English-speaking patients participated in in-depth semi-structured interviews about their experiences of living with Behcet's syndrome. Interviews were recorded and transcribed. Data were analysed using a general inductive thematic approach. RESULTS: Five themes related to the experience of Behcet's syndrome emerged from the interviews: diagnosis (diagnostic challenge and closure), impact of disease (pain, fatigue, reduced vision, fear and uncertainty), loneliness and isolation (lack of support and information, invisible illness), acquiring resilience (coping, gaining sense of control, support group) and ongoing interactions with health system (specialist care, primary care, need for multidisciplinary care, doctor-patient relationship). CONCLUSIONS: Behcet's syndrome patients experience difficulties in obtaining a timely and correct diagnosis and contend numerous physical and emotional challenges, often experiencing loneliness and isolation. Establishing trusting doctor-patient relationships, allowing timely access to specialist care and recruiting psychosocial supports will help patients better cope with their illness. Diagnosis and management of Behcet's syndrome requires close collaboration and communication among specialists and general practitioners and improved education on Behcet's syndrome.

Calcium intake and risk of fracture: systematic review.

OBJECTIVE: To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures. DESIGN: Systematic review of randomised controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses. DATA SOURCES: Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50. RESULTS: There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58,573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48,967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56,648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51,775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger's regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44,505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture. CONCLUSIONS: Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.

Calcium intake and bone mineral density: systematic review and meta-analysis.

OBJECTIVE: To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and, if so, whether the effects are similar to those of calcium supplements. DESIGN: Random effects meta-analysis of randomised controlled trials. DATA SOURCES: Ovid Medline, Embase, Pubmed, and references from relevant systematic reviews. Initial searches were undertaken in July 2013 and updated in September 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of dietary sources of calcium or calcium supplements (with or without vitamin D) in participants aged over 50 with BMD at the lumbar spine, total hip, femoral neck, total body, or forearm as an outcome. RESULTS: We identified 59 eligible randomised controlled trials: 15 studied dietary sources of calcium (n=1533) and 51 studied calcium supplements (n=12,257). Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥ 1000 versus <1000 mg/day and ≤ 500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥ 800 mg/day. CONCLUSIONS: Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture.

Results of observational studies: analysis of findings from the Nurses' Health Study.

BACKGROUND: The role of observational studies in informing clinical practice is debated, and high profile examples of discrepancies between the results of observational studies and randomised controlled trials (RCTs) have intensified that debate. We systematically reviewed findings from the Nurses' Health Study (NHS), one of the longest and largest observational studies, to assess the number and strength of the associations reported and to determine if they have been confirmed in RCTs. METHODS: We reviewed NHS publication abstracts from 1978-2012, extracted information on associations tested, and graded the strength of the reported effect sizes. We searched PubMed for RCTs or systematic reviews for 3 health outcomes commonly reported in NHS publications: breast cancer, ischaemic heart disease (IHD) and osteoporosis. NHS results were compared with RCT results and deemed concordant when the difference in effect sizes between studies was ≤0.15. FINDINGS: 2007 associations between health outcomes and independent variables were reported in 1053 abstracts. 58.0% (1165/2007) were statistically significant, and 22.2% (445/2007) were neutral (no association). Among the statistically significant results that reported a numeric odds ratio (OR) or relative risk (RR), 70.5% (706/1002) reported a weak association (OR/RR 0.5-2.0), 24.5% (246/1002) a moderate association (OR/RR 0.25-0.5 or 2.0-4.0) and 5.0% (50/1002) a strong association (OR/RR ≤0.25 or ≥4.0). 19 associations reported in NHS publications for breast cancer, IHD and osteoporosis have been tested in RCTs, and the concordance between NHS and RCT results was low (≤25%). CONCLUSIONS: NHS publications contain a large number of analyses, the majority of which reported statistically significant but weak associations. Few of these associations have been tested in RCTs, and where they have, the agreement between NHS results and RCTs is poor.