Population-Based Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease.

Pharmacokinetic (PK) data from 28 subjects who received 5-200-mg single ascending doses of ANAVEX3-71, formerly AF710B, were analyzed to characterize the PK of ANAVEX3-71 and its M8 metabolite. PK data from 12 subjects who received 160 mg ANAVEX3-71 under fed and fasted conditions were analyzed to characterize the effect of food on the PK of the drug and its M8 metabolite. PK was characterized using the standard 2-stage approach and the nonlinear mixed-effects modeling approach. Dose proportionality was determined using the power model. Two- and 3-compartment linear PK models were tested for the characterization of the PK of ANAVEX3-71 and its M8 metabolite. The PK of ANAVEX3-71 is linear, dose proportional, and time invariant. The drug is rapidly eliminated with a mean (standard deviation) apparent terminal elimination half-life of 3.56 (4.09) hours, while the M8 metabolite was eliminated with a mean (standard deviation) apparent terminal elimination half-life of 6.59 (1.64) hours. The population PK model was used to investigate the effects of covariates on the PK of ANAVEX3-71 and M8. Age, weight, and creatinine clearance were not explanatory of the variability in apparent clearance and apparent volume of the central compartment of ANAVEX3-71. Food had no effect on the PK of ANAVEX3-71 and its M8 metabolite.

PG545 sensitizes ovarian cancer cells to PARP inhibitors through modulation of RAD51-DEK interaction.

PG545 (Pixatimod) is a highly sulfated small molecule known for its ability to inhibit heparanase and disrupt signaling mediated by heparan-binding-growth factors (HB-GF). Previous studies indicated that PG545 inhibits growth factor-mediated signaling in ovarian cancer (OC) to enhance response to chemotherapy. Here we investigated the previously unidentified mechanisms by which PG545 induces DNA damage in OC cells and found that PG545 induces DNA single- and double-strand breaks, reduces RAD51 expression in an autophagy-dependent manner and inhibits homologous recombination repair (HRR). These changes accompanied the ability of PG545 to inhibit endocytosis of the heparan-sulfate proteoglycan interacting DNA repair protein, DEK, leading to DEK sequestration in the tumor microenvironment (TME) and loss of nuclear DEK needed for HRR. As a result, PG545 synergized with poly (ADP-ribose) polymerase inhibitors (PARPis) in OC cell lines in vitro and in 55% of primary cultures of patient-derived ascites samples ex vivo. Moreover, PG545/PARPi synergy was observed in OC cells exhibiting either de novo or acquired resistance to PARPi monotherapy. PG545 in combination with rucaparib also generated increased DNA damage, increased antitumor effects and increased survival of mice bearing HRR proficient OVCAR5 xenografts compared to monotherapy treatment in vivo. Synergistic antitumor activity of the PG545/rucaparib combination was likewise observed in an immunocompetent syngeneic ID8F3 OC model. Collectively, these results suggest that targeting DEK-HSPG interactions in the TME through the use of PG545 may be a novel method of inhibiting DNA repair and sensitizing cells to PARPis.

The new big is small: Leveraging knowledge from small trials for rare disease drug development: Blarcamesine for Rett syndrome.

Big data in drug development may not satisfactorily address the demands of precision medicine in a rare disease population, making the use of smaller clinical trials necessary. Consequently, the use of innovative design and analysis of these clinical trials using model-informed approaches have become indispensable. This requires informative exposure-outcome analysis, together with formal statistical analysis, which should include the strength of evidence for a study outcome. We demonstrate how knowledge can be gained, with supporting strength of evidence, from a small (data) clinical trial with a low dose of blarcamesine in the treatment of Rett syndrome. Based on a small data paradigm, pharmacometrics item response theory modelling and Bayes factor analysis were used to demonstrate the efficacy of blarcamesine in Rett syndrome.

Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease.

This is the cardiodynamic evaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71, formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1 hour prior to dosing to establish a baseline and then serially postdose. Concentration-QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8 was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8. The estimated population slope of the concentration-QTcF relationship was small and slightly negative: -0.017 ms per µg/L, with a small treatment effect-specific intercept of -0.49 ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10 ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8 up to ∼996 and ∼58 µg/L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200 mg had no clinically relevant effects on any of the studied ECG parameters.

Phase Ib open-label, multicenter study of pixatimod, an activator of TLR9, in combination with nivolumab in subjects with microsatellite-stable metastatic colorectal cancer, metastatic pancreatic ductal adenocarcinoma and other solid tumors.

BACKGROUND: Pixatimod is a unique activator of the Toll-like Receptor 9 pathway. This phase I trial evaluated safety, efficacy and pharmacodynamics of pixatimod and PD-1 inhibitor nivolumab in immunologically cold cancers. METHODS: 3+3 dose escalation with microsatellite stable metastatic colorectal cancer (MSS mCRC) and metastatic pancreatic ductal adenocarcinoma (mPDAC) expansion cohorts. Participants received pixatimod once weekly as a 1-hour intravenous infusion plus nivolumab every 2 weeks. Objectives included assessment of safety, antitumor activity, pharmacodynamics, and pharmacokinetic profile. RESULTS: Fifty-eight participants started treatment. The maximum tolerated dose of pixatimod was 25 mg in combination with 240 mg nivolumab, which was used in the expansion phases of the study. Twenty-one grade 3-5 treatment-related adverse events were reported in 12 participants (21%); one participant receiving 50 mg pixatimod/nivolumab had a treatment-related grade 5 AE. The grade 3/4 rate in the MSS mCRC cohort (n=33) was 12%. There were no responders in the mPDAC cohort (n=18). In the MSS mCRC cohort, 25 participants were evaluable (initial postbaseline assessment scans >6 weeks); of these, three participants had confirmed partial responses (PR) and eight had stable disease (SD) for at least 9 weeks. Clinical benefit (PR+SD) was associated with lower Pan-Immune-Inflammation Value and plasma IL-6 but increased IP-10 and IP-10/IL-8 ratio. In an MSS mCRC participant with PR as best response, increased infiltration of T cells, dendritic cells, and to a lesser extent NK cells, were evident 5 weeks post-treatment. CONCLUSIONS: Pixatimod is well tolerated at 25 mg in combination with nivolumab. The efficacy signal and pharmacodynamic changes in MSS mCRC warrants further investigation. TRIAL REGISTRATION NUMBER: NCT05061017.

An Enzymatic Activity Assay for Heparanase That Is Useful for Evaluating Clinically Relevant Inhibitors and Studying Kinetics.

The enzyme heparanase cleaves heparan sulfate and is involved in a range of human diseases including cancer, inflammation, diabetes, and viral infection. There is a need for a simple and reliable enzymatic assay to allow for the screening of compounds to find inhibitors of heparanase. We have developed an assay that uses the heparinoid fondaparinux as enzyme substrate and detects one of the products of catalysis, which contains a newly formed reducing terminus, with the tetrazolium salt WST-1. Due to the homogenous substrate and single point of cleavage therein, this assay allows for more systematic kinetic analysis of heparanase inhibitors. Here, we provide a detailed method for conducting this assay and also provide information to assist researchers in evaluating whether the assay is performing properly in their laboratories.

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction.

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.

Health care utilization and costs of systemic lupus erythematosus in the United States: A systematic review.

OBJECTIVES: To evaluate health care utilization and costs for patients with systemic lupus erythematosus (SLE) by disease severity. METHODS: We searched PubMed and Embase from January 2000 to June 2020 for observational studies examining health care utilization and costs associated with SLE among adults in the United States. Two independent reviewers reviewed the selected full-text articles to determine the final set of included studies. Costs were converted to 2020 US $. RESULTS: We screened 9224 articles, of which 51 were included. Mean emergency department visits were 0.3-3.5 per year, and mean hospitalizations were 0.1-2.4 per year (mean length of stay 0.4-13.0 days). Patients averaged 10-26 physician visits/year. Mean annual direct total costs were $17,258-$63,022 per patient and were greater for patients with moderate or severe disease ($19,099-$82,391) compared with mild disease ($12,242-$29,233). Mean annual direct costs were larger from commercial claims ($24,585-$63,022) than public payers (Medicare and Medicaid: $18,302-$27,142). CONCLUSIONS: SLE remains a significant driver of health care utilization and costs. Patients with moderate to severe SLE use more health care services and incur greater direct and indirect costs than those with mild disease.

Risk of malignancy in patients with systemic lupus erythematosus: Systematic review and meta-analysis.

BACKGROUND: Malignancy is a potential comorbidity in patients with systemic lupus erythematosus (SLE). However, risk by malignancy type remains to be fully elucidated. We evaluated the risk of malignancy type in SLE patients in a systematic review and meta-analysis. METHODS: MEDLINE and EMBASE were searched from inception to July 2018 to identify observational studies that evaluated malignancy risk in adult SLE patients compared with the general population. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Heterogeneity was quantified using the I2 test. FINDINGS: Forty-one studies reporting on 40 malignancies (one overall, 39 site-specific) were included in the meta-analysis. The pooled RR for all malignancies from 3694 events across 80 833 patients was 1.18 (95% CI: 1.00-1.38). The risk of 24 site-specific malignancies (62%) was increased in SLE patients. For malignancies with ≥6 studies, non-Hodgkin lymphoma and Hodgkin lymphoma risk was increased >3-fold; myeloma and liver >2-fold; cervical, lung, bladder, and thyroid ≥1.5-fold; stomach and brain >1.3-fold. The risk of four malignancies (breast, uterine, melanoma, prostate) was decreased, whereas risk of 11 other malignancies did not differ between SLE patients and the general population. Heterogeneity ranged between 0% and 96%, and 63% were non-significant. INTERPRETATION: The risk of overall and some site-specific malignancies is increased in SLE compared with the general population. However, the risk for some site-specific malignancies is decreased or did not differ. Further examination of risk profiles and SLE patient phenotypes may support guidelines aimed at reducing malignancy risk. FUNDING: AstraZeneca. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number: CRD42018110433.

Health-care utilization and costs in adults with systemic lupus erythematosus in the United Kingdom: a real-world observational retrospective cohort analysis.

OBJECTIVE: The aim was to describe direct health-care costs for adults with SLE in the UK over time and by disease severity and encounter type. METHODS: Patients aged ≥18 years with SLE were identified using the linked Clinical Practice Research Datalink-Hospital Episode Statistics database from January 2005 to December 2017. Patients were classified as having mild, moderate or severe disease using an adapted claims-based algorithm based on prescriptions and co-morbid conditions. We estimated all-cause health-care costs and incremental costs associated with each year of follow-up compared with a baseline year, adjusting for age, sex, disease severity and co-morbid conditions (2017 UK pounds). RESULTS: We identified 802 patients; 369 (46.0%) with mild, 345 (43.0%) moderate and 88 (11.0%) severe disease. The mean all-cause cost increased in the 3 years before diagnosis, peaked in the first year after diagnosis and remained high. The adjusted total mean annual increase in costs per patient was £4476 (95% CI: £3809, £5143) greater in the year of diagnosis compared with the baseline year (P < 0.0001). The increase in costs per year was 4.7- and 1.6-fold higher among patients with severe SLE compared with those with mild and moderate SLE, respectively. Primary care utilization was the leading component of costs during the first year after diagnosis. CONCLUSION: The health-care costs for patients with SLE in the UK are substantial, remain high after diagnosis and increase with increasing severity. Future research should assess whether earlier diagnosis and treatment might reduce disease severity and associated high health-care costs.

Frequency, severity and costs of flares increase with disease severity in newly diagnosed systemic lupus erythematosus: a real-world cohort study, United States, 2004-2015.

OBJECTIVE: To evaluate frequency, severity and costs of flares in US patients with newly diagnosed SLE. METHODS: Adults diagnosed with SLE between January 2005 and December 2014 were identified from US commercial claims data linked to electronic medical records. Disease and flare severity during 1 year after diagnosis were classified as mild, moderate or severe using a claims-based algorithm. Study outcomes included frequency and severity of flares stratified by disease severity during the 1-year post-diagnosis period and all-cause healthcare costs of flares by severity at 30, 60 and 90 days after flare. RESULTS: Among 2227 patients, 26.3%, 51.0% and 22.7% had mild, moderate and severe SLE, respectively. The overall annual flare rate was 3.5 and increased with disease severity: 2.2, 3.7 and 4.2, respectively, for mild, moderate and severe SLE (p<0.0001). Patients with severe SLE had a higher annual severe flare rate (0.6) compared with moderate (0.1) or mild SLE (0; p<0.0001). Mean total all-cause costs at 30, 60 and 90 days after flare were $16 856, $22 252 and $27 468, respectively, for severe flares (mild flares: $1672, $2639 and $3312; moderate flares: $3831, $6225, $8582; (p<0.0001, all time points)). Inpatient costs were the primary driver of the increased cost of severe flares. CONCLUSIONS: Flare frequency and severity in newly diagnosed patients with SLE increase with disease severity. After a flare, healthcare costs increase over the following 90 days by disease severity. Preventing flares or reducing flare rates and duration may improve outcomes and reduce healthcare costs.

Disease severity, flares and treatment patterns in adults with systemic lupus erythematosus in the UK: a real-world observational retrospective cohort analysis.

OBJECTIVES: The aim was to characterize disease severity, clinical manifestations, treatment patterns and flares in a longitudinal cohort of adults with SLE in the UK. METHODS: Adults with SLE were identified in the Clinical Practice Research Datalink-Hospital Episode Statistics database (1 January 2005-31 December 2017). Patients were required to have ≥12 months of data before and after the index date (earliest SLE diagnosis date available). SLE disease severity and flares were classified using adapted claims-based algorithms, which are based on SLE-related conditions, medications and health-service use. RESULTS: Of 802 patients, 369 had mild, 345 moderate and 88 severe SLE at baseline. A total of 692 initiated treatment in the first year after diagnosis. Five hundred and fifty-seven received antimalarials, 203 immunosuppressants and 416 oral CSs. Information on biologic use in hospitals was unavailable. The mean (S.d.) time to initiating any medication was 177 (385.3) days. The median time to first flare was 63 days (95% CI: 57, 71). At least one flare was experienced by 750 of 802 patients during follow-up; the first flare was mild for 549 of 750, moderate for 116 of 750 and severe for 85 of 750. The mean (S.d.) annual overall flare rate (year 1) was 3.5 (2.5). A shorter median time to first flare was significantly associated with moderate/severe disease (P < 0.001) and clinical manifestations (P < 0.001). CONCLUSION: Our findings suggest some delay in the initiation of SLE treatment. Most patients experience a flare within 2 months of diagnosis. Early treatment might delay or reduce the severity of the first SLE flare and might translate to slower disease progression, lower accrual of organ damage and better outcomes.

Disease and economic burden increase with systemic lupus erythematosus severity 1 year before and after diagnosis: a real-world cohort study, United States, 2004-2015.

OBJECTIVE: To assess the economic burden of patients with SLE by disease severity in the USA 1 year before and after diagnosis. METHODS: Patients aged ≥18 years with a first SLE diagnosis (index date) between January 2005 and December 2014 were identified from administrative commercial claims data linked to electronic medical records (EMRs). Disease severity during the year after diagnosis was classified as mild, moderate, or severe using claims-based algorithms and EMR data. Healthcare resource utilisation (HCRU) and all-cause healthcare costs (2017 US$) were reported for 1 year pre-diagnosis and post-diagnosis. Generalised linear modelling examined all-cause costs over 1 year post-index, adjusting for baseline demographics, clinical characteristics, Charlson Comorbidity Index and 1 year pre-diagnosis costs. RESULTS: Among 2227 patients, 26.3% had mild, 51.0% moderate and 22.7% severe SLE. Mean per-patient costs were higher for patients with moderate and severe SLE compared with mild SLE during the year before diagnosis: mild US$12 373, moderate $22 559 and severe US$39 261 (p<0.0001); and 1-year post-diagnosis period: mild US$13 415, moderate US$29 512 and severe US$68 260 (p<0.0001). Leading mean cost drivers were outpatient visits (US$13 566) and hospitalisations (US$10 252). Post-diagnosis inpatient utilisation (≥1 stay) was higher for patients with severe (51.2%) and moderate (22.4%) SLE, compared with mild SLE (12.8%), with longer mean hospital stays: mild 0.47 days, moderate 1.31 days and severe 5.52 days (p<0.0001). CONCLUSION: HCRU and costs increase with disease severity in the year before and after diagnosis; leading cost drivers post-diagnosis were outpatient visits and hospitalisations. Earlier diagnosis and treatment may improve health outcomes and reduce HCRU and costs.

Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain.

SARS-CoV-2 has rapidly spread throughout the world's population since its initial discovery in 2019. The virus infects cells via a glycosylated spike protein located on its surface. The protein primarily binds to the angiotensin-converting enzyme-2 (ACE2) receptor, using glycosaminoglycans (GAGs) as co-receptors. Here, we performed bioinformatics and molecular dynamics simulations of the spike protein to investigate the existence of additional GAG binding sites on the receptor-binding domain (RBD), separate from previously reported heparin-binding sites. A putative GAG binding site in the N-terminal domain (NTD) of the protein was identified, encompassing residues 245-246. We hypothesized that GAGs of a sufficient length might bridge the gap between this site and the PRRARS furin cleavage site, including the mutation S247R. Docking studies using GlycoTorch Vina and subsequent MD simulations of the spike trimer in the presence of dodecasaccharides of the GAGs heparin and heparan sulfate supported this possibility. The heparan sulfate chain bridged the gap, binding the furin cleavage site and S247R. In contrast, the heparin chain bound the furin cleavage site and surrounding glycosylation structures, but not S247R. These findings identify a site in the spike protein that favors heparan sulfate binding that may be particularly pertinent for a better understanding of the recent UK and South African strains. This will also assist in future targeted therapy programs that could include repurposing clinical heparan sulfate mimetics.

The Burden of Systemic Lupus Erythematosus in Germany: Incidence, Prevalence, and Healthcare Resource Utilization.

INTRODUCTION: We evaluated incidence, prevalence, costs, and healthcare utilization associated with systemic lupus erythematosus (SLE) in patients in Germany. METHODS: Adult patients with SLE were identified from the German Betriebskrankenkassen (BKK) health insurance fund database between 2009 and 2014. SLE incidence and prevalence were calculated for each year and extrapolated (age and sex adjusted) to the German population. The 2009 SLE population was followed through 2014. Healthcare utilization and costs for patients with SLE were calculated and compared with controls matched by age, sex, and baseline Charlson Comorbidity Index scores. RESULTS: This analysis included 1160 patients with SLE. Estimated SLE incidence between 2009 and 2014 ranged from 4.59 to 6.89 per 100,000 persons and prevalence ranged from 37.32 to 47.36 per 100,000. SLE incidence in Germany in 2014 was 8.82 per 100,000 persons; prevalence was 55.80 (corrected for right-censored data). At baseline, 12.8, 41.7, and 45.5% of patients were categorized as having mild, moderate, and severe SLE, respectively. Patients with SLE had greater mean (standard deviation [SD]) annual medical costs compared with matched controls 1 year after index diagnosis (€6895 [14,424] vs. €3692 [3994]; P < 0.0001) and in subsequent years. Patients with moderate or severe SLE had significantly more hospitalizations, outpatient visits, and prescription medication use compared with matched controls. Mean annual costs for 5 years ranged from €1890 to 3010, €4867 to 5876, and €8396 to 10,001 for patients with mild, moderate, and severe SLE, respectively. CONCLUSIONS: SLE incidence in Germany increased 1.4-fold over 5 years. Patients with SLE have higher healthcare costs, and costs increase with baseline severity. Early and effective treatments may delay progression and reduce the burden of SLE.

Healthcare Utilization and Costs of Systemic Lupus Erythematosus by Disease Severity in the United States.

OBJECTIVE: To quantify healthcare utilization and costs by disease severity for patients with systemic lupus erythematosus (SLE) in the United States. METHODS: We conducted descriptive analyses of Humedica electronic health record (EHR) data from 2011 to 2015 (utilization analysis) and integrated Optum administrative claims/Humedica EHR data from 2012 to 2015 (cost analysis) for patients with SLE. All-cause utilization outcomes examined were hospitalizations, outpatient visits, emergency department (ED) visits, and prescription drug use. Analyses of costs stratified by disease severity were limited to patients enrolled in an Optum-participating health insurance plan for ≥ 1 year after the earliest observed SLE diagnosis date. Costs were converted to 2016 US dollars (US$). RESULTS: Healthcare utilization was evaluated in 17,257 patients with SLE. Averaged over the 2011-2015 study period, 13.7% of patients had ≥ 1 hospitalization per year, 25.7% had ≥ 1 ED visit, and 94.4% had ≥ 1 outpatient visit. Utilization patterns were generally similar across each year studied. Annually, 88.0% of patients had ≥ 1 prescription, including 1.3% who used biologics. Biologic treatment doubled between 2011 (0.7%) and 2015 (1.4%). Cost analyses included 397 patients. From 2012 to 2015, patients with severe SLE had mean annual costs of $52,951, compared with $28,936 and $21,052 for patients with moderate and mild SLE, respectively. Patients with severe SLE had increased costs in all service categories: inpatient, ED, clinic/office visits, and pharmacy. CONCLUSION: Patients from the US with SLE, especially individuals with moderate or severe disease, utilize significant healthcare resources and incur high medical costs.

The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis to determine the magnitude of infection risk in patients with SLE and evaluate the effect of general and SLE-related factors on infection risk. METHODS: We searched MEDLINE and Embase from inception to July 2018, screening for observational studies that evaluated infection risk in patients with SLE compared with the general population/healthy controls. Outcomes of interest included overall severe infection, herpes zoster infection/reactivation, opportunistic infections, pneumonia and tuberculosis. Random-effects models were used to calculate pooled risk ratios (RRs) for each type of infection. Sensitivity analysis assessed the impact of removing studies with high risk of bias. RESULTS: Eleven retrospective or prospective cohort studies were included in the meta-analysis: overall severe infection (n = 4), pneumonia (n = 6), tuberculosis (n = 3) and herpes zoster (n = 2). Pooled RRs for overall severe infection significantly increased for patients with SLE compared with the general population/healthy controls [RR 2.96 (95% CI 1.28, 6.83)]. Pooled RRs for pneumonia, herpes zoster and tuberculosis showed significantly increased risk compared with the general population/healthy controls [RR 2.58 (1.80, 3.70), 2.50 (2.36, 2.65) and 6.11 (3.61, 10.33), respectively]. Heterogeneity and evidence of publication bias were present for all analyses, except herpes zoster. Sensitivity analyses confirmed robustness of the results. CONCLUSION: Patients with SLE have significantly higher risk of infection compared with the general population/healthy controls. Efforts to strengthen strategies aimed at preventing infections in SLE are needed. PROTOCOL REGISTRATION: PROSPERO number: CRD42018109425.

Systemic lupus erythematosus; stroke and myocardial infarction risk: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the risk of stroke and myocardial infarction (MI) in adult patients with systemic lupus erythematosus (SLE) through a systematic review and meta-analysis. METHODS: We searched MEDLINE and EMBASE from inception to May 2020 to identify observational studies (cohort and cross-sectional) that evaluated risk of stroke and MI in adult patients with SLE compared with the general population or healthy controls. Studies were included if they reported effect-size estimates that could be used for calculating pooled-effect estimates. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% CIs for stroke and MI. Heterogeneity quantified by the I2 test and sensitivity analyses assessed bias. RESULTS: In total, 26 studies were included in this meta-analysis: 14, 5 and 7 studies on stroke, MI and both stroke and MI, respectively. The pooled RR for ischaemic stroke was 2.18 (95% CI 1.78 to 2.67; I2 75%), intracerebral haemorrhage 1.84 (95% CI 1.16 to 2.90; I2 67%), subarachnoid haemorrhage 1.95 (95% CI 0.69 to 5.52; I2 94%), composite stroke 2.13 (95% CI 1.73 to 2.61; I2 88%) and MI 2.99 (95% CI 2.34 to 3.82; I2 85%). There was no evidence for publication bias, and sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: Overall, patients with SLE were identified to have a twofold to threefold higher risk of stroke and MI. Future research on the interaction between known SLE-specific modifiable risk factors and risk of stroke and MI to support development of prevention and treatment strategies are needed. PROSPERO REGISTRATION NUMBER: CRD42018098690.

Study protocol for the international Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS): understanding lupus and the role of type I interferon gene signature.

INTRODUCTION: The Systemic Lupus Erythematosus (SLE) Prospective Observational Cohort Study (SPOCS) aims to describe the disease course of SLE and its association with type I interferon gene signature (IFNGS) status. METHODS AND ANALYSIS: SPOCS is an international, multicentre, prospective, observational cohort study designed to follow patients through biannual study visits during a 3-year observation period. Patients ≥18 years old with a physician diagnosis that meets the American College of Rheumatology or Systemic Lupus International Collaborating Clinics SLE classification criteria will be included. SPOCS will comprehensively analyse clinical features, disease progression and treatment, SLE outcomes, health status assessments and quality of life, and healthcare resource utilisation of patients with moderate to severe SLE. A four-gene test will be used to measure IFNGS status; scores will be compared with a pre-established cut-off. Patients will be stratified by low or high IFNGS expression levels. Enrolment began in June 2017, and study completion is expected in 2022. The total number of anticipated patients was initially planned for 1500 patients and was amended to 900 patients owing to slow accrual of eligible patients. ETHICS AND DISSEMINATION: The ethics committee/institutional review board/independent ethics committee at each study site approved the SPOCS protocol prior to study initiation (protocol number: D3461R00001, version 3.0, 26 June 2019). Study findings will be disseminated through peer-reviewed publications and presentations at scientific meetings. TRIAL REGISTRATION NUMBER: NCT03189875.