Faculty Bibliography

Background: Primary Sjogren's syndrome (pSS) is a systemic progressive autoimmune disease characterised by formation of lymphoid structures and germinal centres within glandular tissue. Iscalimab (CFZ533) is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor important for germinal centre reactions and B cell activation. Iscalimab showed clinical efficacy in a Proof of Concept randomised controlled trial at a dose of 10 mg/kg intravenously (IV), whereas subcutaneous (SC) dosing at 3 mg/kg was associated with unexpectedly low plasma concentrations and reduced efficacy, likely due to efficient pre-systemic target-mediated clearance.
Objective(s): To test IV versus SC loading doses of iscalimab followed by SC maintenance dosing, as a means of achieving target drug exposure and clinical efficacy.
Method(s): Patients with clinically active pSS [EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) >=6] were randomised to receive either 600 mg SC iscalimab weekly on 4 occasions, followed by 300 mg SC weekly until week 12, or a single IV dose of 10 mg/kg iscalimab on study Day 1, followed by 300 mg SC weekly until week 12. Subjects and investigator staff remained blinded to study treatment allocation until first dosing.
Result(s): Twenty-five patients were randomised; 13 in the SC loading and 12 in the IV loading arms. Baseline characteristics were similar to the previous phase IIa cohorts with mean ESSDAI scores of 12.7 (SD 6.1) and 10.4 (5.9) in the SC and IV loading arms respectively. In Arm 1 (SC) and Arm 2 (IV), the mean trough plasma concentrations were 169mug/mL (SD 64.1, CV 38%) and 135mug/mL (SD 70.9, CV 53%) on Day 85, respectively. Both values were well above levels previously reported to be sufficient for suppression of germinal centre development and T dependent antigen responses in cynomolgus monkeys. Consistent with this finding, clinically important improvements were seen in both arms with a mean decrease in ESSDAI scores of -5.5 (+/- SD: 5.5) and -7.6 (+/- 7.1) points from baseline to Day 85 in the SC and IV dosing arms. Improvements were also seen in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) scores: -1.67 (+/- 1.8) and -1.17 (+/- 2.3), respectively. Other secondary efficacy outcomes showed similar patterns of improvement. Treatment with iscalimab was associated with a reduction in the germinal centre-related serum biomarker CXCL13 in both groups. Overall, iscalimab was safe and well-tolerated with no new safety signal emerging. One subject experienced three SAEs (hemarthrosis, worsening of right knee pain and swelling requiring arthroscopy) in the safety followup period, all unrelated to study drug.
Conclusion(s): These results further support the safety and efficacy of iscalimab in pSS and the suitability of SC dosing for future development

We report the case of a dyspneic patient with a five-liter pleural empyema that was diagnosed and managed in a resource-limited clinic in a rural part of Sierra Leone. The diagnosis and management of this condition are usually guided by imaging modalities such as X-rays or CT scans. However, these resources may not be available in austere settings in developing countries. Because emergency physicians work in a variety of clinical settings, they should be well versed in the use of portable ultrasound machines to diagnose, treat, and manage many different conditions.

STUDY OBJECTIVE: Patients in the third trimester of pregnancy presenting to the emergency department (ED) with hypotension are routinely placed in the left lateral tilt (LLT) position to relieve inferior vena cava (IVC) compression from the gravid uterus thereby increasing venous return. However, the relationship between patient position and proximal intrahepatic IVC filling has never assessed directly. This study set out to determine the effect of LLT position on intrahepatic IVC diameter in third trimester patients under real-time visualization with ultrasound. METHODS: This prospective observational study on the labor and delivery floor of a large urban academic teaching hospital enrolled patients between 30 and 42 weeks estimated gestational age from August 2011 to March 2012. Patients were placed in three different positions: supine, LLT, and right lateral tilt (RLT). After the patient was in each position for at least 3 min, IVC ultrasound using the intercostal window was performed by one of three study sonologists. Maternal and fetal hemodynamics were also monitored and recorded in each position. RESULTS: A total of 26 patients were enrolled with one excluded from data analysis due to inability to obtain IVC measurements. The median IVC maximum diameter was 1.26 cm (95% confidence interval [CI] 1.13-1.55) in LLT compared to 1.13 cm (95% CI 0.89-1.41) in supine, p=0.01. When comparing each individual patient's LLT to supine measurement, LLT lead to an increase in maximum IVC diameter in 76% (19/25) of patients with the average LLT measurement 29% (95% confidence interval 10-48%) larger. Six patients had the largest maximum IVC measurement in the supine position. No patients experienced any hemodynamic instability or distress during the study. CONCLUSION: IVC ultrasound is feasible in late pregnancy and demonstrates an increase in diameter with LLT positioning. However, a quarter of patients had a decrease in IVC diameter with tilting and, instead, had the largest IVC diameter in the supine position suggesting that uterine compression of the IVC may not occur universally. IVC assessment at the bedside may be a useful adjunct in determining optimal positioning for resuscitation of third trimester patients.

Retained foreign objects account for as much as 2% of soft tissue injuries sustained in the wilderness. Subcutaneously embedded fragments are often missed during the initial medical evaluation and may result in morbidity secondary to delayed removal. Although the utility of ultrasonography in the emergency department for the detection of retained objects is established, the potential use of point-of-care ultrasound to aid with foreign body removal in the field has not been well described. We present 2 case reports that demonstrate the value of ultrasonography in detecting and successfully removing foreign bodies sustained in the wilderness, and outline a procedural technique that minimizes morbidity and uses equipment available in wilderness medical field kits. We propose that with the advent of portable and handheld ultrasound units, foreign body removal in the field has become feasible and may decrease the morbidity of soft tissue injuries, particularly in austere and wilderness environments with limited access to immediate medical care.

STUDY OBJECTIVES: Obtaining intravenous (IV) access in the emergency department (ED) can be especially challenging, and physicians often resort to placement of central venous catheters (CVCs). Use of ultrasound-guided peripheral IV catheters (USGPIVs) can prevent many "unnecessary" CVCs, but the true impact of USGPIVs has never been quantified. This study set out to determine the reduction in CVCs by USGPIV placement. METHODS: This was a prospective, observational study conducted in 2 urban EDs. Patients who were to undergo placement of a CVC due to inability to establish IV access by other methods were enrolled. Ultrasound-trained physicians then attempted USGPIV placement. Patients were followed up for up to 7 days to assess for CVC placement and related complications. RESULTS: One hundred patients were enrolled and underwent USGPIV placement. Ultrasound-guided peripheral IV catheters were initially successfully placed in all patients but failed in 12 patients (12.0%; 95 confidence interval [CI], 7.0%-19.8%) before ED disposition, resulting in 4 central lines, 7 repeated USGPIVs, and 1 patient requiring no further intervention. Through the inpatient follow-up period, another 11 patients underwent CVC placement, resulting in a total of 15 CVCs (15.0%; 95 CI, 9.3%-23.3%) placed. Of the 15 patients who did receive a CVC, 1 patient developed a catheter-related infection, resulting in a 6.7% (95 CI, 1.2%-29.8%) complication rate. CONCLUSION: Ultrasound prevented the need for CVC placement in 85% of patients with difficult IV access. This suggests that USGPIVs have the potential to reduce morbidity in this patient population.

Th1 cells have different capacities to develop into memory cells based on their production of IFN-gamma. In this study, the mechanism by which a homogenous population of IFN-gamma-producing CD4 T cells was eliminated in vivo was assessed. When such cells were transferred into naive mice and activated with Ag, a striking decrease in the frequency of cells in the spleen and lung was observed. However, administration of neutralizing anti-IFN-gamma Ab at the time of Ag challenge largely prevented the elimination of such cells. To determine whether IFN-gamma was mediating its effects directly and/or indirectly, the ability of IFN-gamma to effectively signal in such cells was assessed in vitro. Indeed, there was reduced phosphorylation of STAT1 in response to IFN-gamma as well as markedly reduced expression of the IFN-gammaR beta-chain. Furthermore, transfer of such cells into IFN-gammaR-deficient mice limited their death following activation with Ag. Together, these data suggest that IFN-gamma acts in a paracrine manner to mediate the death of activated IFN-gamma-producing Th1 cells. In contrast to Ag stimulation, administration of CpG alone resulted in the elimination of Th1 cells in IFN-gammaR-/- mice. These results show that in response to Ag stimulation, the death of IFN-gamma-producing effector Th1 cells is controlled in an IFN-gamma-dependent manner, whereas in response to innate activation, the death of IFN-gamma-producing Th1 cells can occur through an IFN-gamma-independent pathway. Collectively, these data show the multiple mechanisms by which Th1 effector cells are efficiently eliminated in vivo.

IL-10 is an important immunoregulatory cytokine that plays a central role in maintaining a balance between protective immunity against infection and limiting proinflammatory responses to self or cross-reactive Ags. We examined the full effects of IL-10 deficiency on the establishment and quality of T cell memory using murine listeriosis as a model system. IL-10(-/-) mice had reduced bacterial loads and a shorter duration of primary infection than did wild-type mice. However, the number of Ag-specific T cells in secondary lymphoid and nonlymphoid organs was diminished in IL-10(-/-) mice, compared with wild-type mice, at the peak of the effector response. Moreover, the frequency and protective capacity of memory T cells also were reduced in IL-10(-/-) mice when assessed up to 100 days postinfection. Remarkably, this effect was more pronounced for CD8 T cells than CD4 T cells. To address whether differences in the number of bacteria and duration of primary infection could explain these findings, both strains of mice were treated with ampicillin 24 hours after primary infection. Despite there being more comparable bacterial loads during primary infection, IL-10(-/-) mice still generated fewer memory CD8 T cells and were less protected against secondary infection than were wild-type mice. Finally, the adoptive transfer of purified CD8 T cells from previously infected wild-type mice into naive recipients conferred better protection than the transfer of CD8 T cells from immune IL-10(-/-) mice. Overall, these data show that IL-10 plays an unexpected role in promoting and/or sustaining CD8 T cell memory following Listeria monocytogenes infection.

Signaling through the high affinity IgE receptor is initiated by noncovalently associated Lyn kinase, resulting in the secretion of inflammatory mediators from mast cells. A fraction of the total cellular Lyn is associated via its N-terminal unique domain with the cytoplasmic domain of the Fc epsilonRI beta subunit before receptor aggregation. In the current study, we stably transfected the unique domain of Lyn into rat basophilic leukemia-2H3 mast cells and examined the consequences on Fc epsilonRI-induced signal transduction and mediator secretion to further define the role of the unique domain of Lyn in mast cell secretion. Tyrosine phosphorylation of Fc epsilonRI beta and gamma subunits was partially inhibited in the Lyn unique domain transfectants after Ag stimulation. Ag stimulation of Lyn unique domain transfectants was accompanied by enhanced phosphorylation of MEK and ERK-2, which are required for leukotriene C4 (LTC4) release, and production of LTC4 was increased 3- to 5-fold, compared with cells transfected with vector alone. Conversely, tyrosine phosphorylation of the adaptor protein Gab2, which is essential for mast cell degranulation, was inhibited after Ag stimulation of Lyn unique domain transfectants, and Ag-induced release of histamine was inhibited up to 48%. In rat basophilic leukemia-2H3 cells, Lyn thus plays a dual role by positively regulating Fc epsilonRI phosphorylation and degranulation while negatively regulating LTC4 production. This study provides further evidence that the constitutive interaction between the unique domain of Lyn and the Fc epsilonRI beta subunit is a crucial step in the initiation of Fc epsilonRI signaling and that Lyn is limiting for Fc epsilonRI-induced secretion of inflammatory mediators.