An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the 'Save PDF' action button.
Abstract In mammalian systems, platelet‐activating factor, 1‐ O ‐alkyl‐2‐acetyl‐ sn ‐glycero‐3‐phosphocholine, (PAF) is rapidly inactivated by a deacetylation/reacylation system that produces 1‐ O ‐alkyl‐2‐acyl‐ sn ‐glycero‐3‐phosphocholine which is highly enriched in arachidonic acid. There is some evidence that n−3 fatty acids may have an impact on this system in humans but the nature of this impact is unclear. In rainbow trout, n−3 fatty acids are known to be essential dietary components which are derived through the food chain. Substantial quantities of n−3 fatty acids are found in trout membrane phospholipids. We show here that in sharp contrast to mammalian cells, trout cells acylate lyso platelet‐activating factor, alkyl‐GPC, 1‐ O ‐alkyl‐2‐lyso‐ sn ‐glycero‐3‐phosphocholine, (lyso‐PAF) with a high degree of specificity for n−3 fatty acids. When [ 3 H]lysoPAF was incubated with these cells, only three molecular species of alkylacylglycerophosphocholine were produced, and 92% contained n−3 fatty acids. Since isolated membranes yielded similar results, it appears that the acylation proceeds via a coenzyme A‐independent transacylase as found in mammalian systems.
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare autoimmune disease characterised by vascular inflammation and multisystem organ damage. There is no commonly accepted set of diagnostic criteria for EGPA, with the Chapel Hill Consensus Conference definition, 1990 American College of Rheumatology (ACR) classification criteria and the 2022 ACR-EULAR classification criteria all used. In addition, International Classification of Diseases coding can be used to identify patients. A previous systematic review reported incidence and prevalence of EGPA with searches to June 2019; however, the recent introduction of biologics that target eosinophils may have an impact on diagnosis rates and outcomes.
Objectives:
To update and extend the systematic review of EGPA epidemiology.
Methods:
Searches were conducted in Ovid MEDLINE and Ovid Embase from January 2019 to June 2023 to provide the most recent data, without language restrictions. Relevant conferences and SLR bibliographies from 2020–2023 were hand searched. Risk of bias assessments on the main publication for each included full-text study were conducted with validated tools. This review has been registered with PROSPERO.[1] Frequentist meta-analyses were conducted using random effects models to generate pooled estimates for EGPA mortality, incidence and prevalence.
Results:
From a total of 1,815 records, 90 publications were included, which reported 69 unique studies. All-cause mortality was reported by 14 studies suitable for meta-analysis, and ranged from 0% to 17.6% across median follow-up times from three months to ten years. One database study reported 17.6% mortality in 767 patients with EGPA compared to 7.4% in age- and sex-matched controls, while a physician survey reported a 10-year mortality rate of 25% in patients with EGPA who are glucocorticoid dependent and 40% in patients with relapsed or refractory disease compared to 10% in the overall EGPA cohort. Prognostic factors with a statistically significantly increased risk of death included older age at onset, more severe and active disease and cardiac or cerebrovascular involvement (three studies). The pooled estimate for EGPA mortality was 10.63 per 1,000 person-years (95% confidence interval [CI]; 7.20, 15.71) (Figure 1A). Five studies reported incidence, ranging from 0.6 to 7.5 cases per million person-years. The pooled estimate for EGPA incidence was 2.03 cases per million person-years (95% CI; 0.97, 4.26 [Figure 1B]). Prevalence was reported by nine studies and ranged widely from 9.0 to 58.6 cases per million people. An increase in prevalence was observed over time (seven studies). The pooled estimate for EGPA prevalence was 34.44 per million people (95% CI; 22.92, 51.76 [Figure 1C]).
Conclusion:
The findings from this study are similar to previous reports [2] confirming that EGPA has a low incidence and prevalence, consistent with the rare nature of the disease. Data suggest that EGPA is more prevalent now compared to 5–10 years ago, which may reflect improved awareness, increased diagnosis and better treatment of the disease resulting in patients living longer. Reported mortality rates vary, but may be higher than the general population, particularly in patients who are glucocorticoid-dependent or with relapsed/refractory disease.
REFERENCES:
[1] National Institute for Health and Care Research. Epidemiology of eosinophilic granulomatosis with polyangiitis (EGPA): a systematic review (PROSPERO registration number: CRD42023432025). 2023. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=432025 [accessed 15 November 2023]. [2] Jakes RW, Kwon N, Nordstrom B, et al. Burden of illness associated with eosinophilic granulomatosis with polyangiitis: a systematic literature review and meta-analysis. Clin Rheumatol. 2021;40(12):4829-36.
Acknowledgements:
The authors thank Victoria Richardsdóttir Fife and Bianca Kennedy Hall from AstraZeneca for project support, and Sukhvir Rai and Kerrie Ford of Health Economics and Outcomes Research Ltd (Cardiff, UK) for medical writing support, which was funded by AstraZeneca (Cambridge, UK) in accordance with Good Publication Practice (GPP 2022) guidelines (https://www.ismpp.org/gpp-2022).
Disclosure of Interests:
Jennifer Rowell owns share options in AstraZeneca and Roche, employee of AstraZeneca, but previously employed by Roche, Amgen and QLT Phototherapeutics, Sara Lucas an employee of Health Economics and Outcomes Research Ltd. Health Economics and Outcomes Research Ltd. received funding for data analysis and medical writing support from AstraZeneca for this work, Matthew Turner an employee of Health Economics and Outcomes Research Ltd. Health Economics and Outcomes Research Ltd. received funding for data analysis and medical writing support from AstraZeneca for this work, Paul Dolin contractor for AstraZeneca.
Purpose: Methods: TREAT, a prospective registry, evaluated the long-term safety of infliximab (IFX) and other therapies in CD. Results: 6273 pts were enrolled: 3396 received IFX (14184 pt-yrs; 86.7% ≥2 infusions) and 2877 received other therapies only (10391 pt-yrs) with a mean follow-up of 4.3 yrs. More IFX-treated pts had moderate-to-severe (30.7% vs 10.8%, P < 0.0001) or severe-fulminant (2.5% vs 0.6%, P < 0.0001) CD at registration, had been hospitalized (27.3% vs 18.9%, P < 0.0001) in the yr prior to enrollment, and were taking prednisone (26.8% vs 16.0%, P < 0.0001) or immunomodulators (49.0% vs 31.7%, P < 0.0001) at enrollment. Infusion reactions occurred in 3.3% of 43,806 infusions; severe reactions in 0.08%. Mortality was similar for both IFX- and non-IFX-treated pts (0.62 per 100 pt-yrs vs 0.58; RR = 1.06,95%CI = 0.78–1.45). In an adjusted Cox proportional hazards analysis, prednisone (HR = 1.86, CI = 1.31–2.64, P < 0.001) and narcotic use (HR = 2.11, CI = 1.47–3.02, P < 0.001) were associated with increased mortality risk. Disease severity (HR = 1.51,95%CI = 1.04–2.19, P= 0.03) was predictive of mortality. The incidence of malignancies in the grps was similar (0.43 per 100 pt-yrs in IFX pts vs 0.56 in non-IFX pts; RR = 0.76,95% CI = 0.54–1.07), as was the incidence of lymphoma (0.04 per 100 pt-yrs in IFX pts vs 0.05 in non-IFX pts; RR = 0.74,95%CI = 0.24–2.29). The incidence of serious infections (SI) was 1.01 per 100 pt-yrs within 3 mos of IFX and 0.64 not within 3 mos of IFX (RR = 1.57,95%CI = 1.16–2.14, P= 0.004). The unadjusted rates per 100 pt-yrs were 1.60 in the IFX grp and 0.67 in the other-treatments-only grp (P < 0.001). An adjusted Cox analysis, using medication exposure at any time prior to the event, showed IFX was not a statistically significant predictor of SI (HR = 1.37,95%CI = 0.96–1.97, P= 0.09). Medications associated with SI were prednisone (HR = 1.75, CI = 1.25–2.44, P < 0.001) and narcotics (HR = 1.96, 95%CI = 1.40–2.75, P < 0.001). Using multivariable Cox proportional hazards regression model and medication exposure in the prior 6-month CRF data collection period, use of prednisone (HR = 2.11, 95%CI 1.49–3.00, P < 0.001) and use of narcotic analgesics (HR = 2.21,95%CI 1.50–3.25, P < 0.001) remain highly significant predictors of SI. There was a notable trend toward IFX being a predictor of SI (HR = 1.373, 95%CI 0.987–1.910, P= 0.06). To date, 1 IFX-treated pt with known latent TB, who did not receive adequate prophylaxis, developed active TB. Conclusion: Despite having more severe CD, IFX pts had similar rates of mortality and malignancy, including lymphoma, as pts not treated with IFX. IFX-treated pts have an increased risk of SI but Cox proportional hazard analysis suggests that this increased risk is independently associated with prednisone and narcotic use, and not IFX.
e22001 Background: Pediatric ALL is the most common childhood leukemia, 20% of children relapse after initial complete response (CR) to first-line treatment and the 5-year overall survival (OS) of pediatric r/r ALL patients is only 30%. A systematic literature review (SLR) and meta-analysis (MA) were conducted to determine the effects of treatments for pediatric r/r ALL. Methods: EMBASE, MEDLINE, and CENTRAL databases were searched from 01/01/2000-12/31/2016 using keywords for r/r ALL paired with terms for pediatric patients and relevant treatments to identify studies reporting efficacy and safety data. Proceedings from 2015-2016 oncology conferences were also searched. Statistical analysis was limited to studies with comparable patient populations and treatment regimens. Random-effects MA of single-arm data were performed to determine the OS rate at 6 and 12 months, median OS, and the rate of CR (timepoint not reported) for pediatric r/r ALL patients treated with clofarabine + cyclophosphamide + etoposide (CCE). Results: The studies included in the review were heterogeneous and just five of the 46 studies identified by the SLR were similar enough for MA in terms of outcomes and populations (median age 8-14 years, median 2 prior lines of therapy). All five studies were single-arm studies evaluating CCE, a treatment with a pooled 6-month OS of 43.5% (95% CI: 32.6% - 55.1%), 1-year OS of 26.7% (95% CI: 17.5% - 38.3%), and pooled median OS of 5.2 (95% CI: 3.2 – 8.6) months. The CR rate was 43.2% (33.7% - 53.3%) across the five studies (timepoint not reported), and the rate was comparatively higher when analysis was limited to those with B-cell immunophenotype (56.3% [95% CI: 22.5% - 85.1%]). Conclusions: This is the first SLR and MA to be conducted on pediatric r/r ALL to date. Available evidence was heterogeneous and MA were only possible for single-arm trials examining CCE. Survival is poor in this population, as just over a quarter of patients receiving CCE were alive at 12 months, with median OS less than 6 months. CR rates were more promising but the lack of data on timepoint of assessment make the results difficult to interpret. New treatments are needed to better manage patients in this r/r population.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
