Objective
To provide updated American College of Rheumatology (ACR) recommendations on rheumatoid arthritis (RA) disease activity measurements to facilitate a treat‐to‐target approach in routine ...clinical care.
Methods
A working group conducted a systematic literature review from the time of the prior ACR recommendations literature search. Properties of disease activity measures were ed, and study quality was assessed using the Consensus‐Based Standards for the selection of Health Measurement Instruments 4‐point scoring method, allowing for overall level of evidence assessment. Measures that fulfilled a minimum standard were identified, and through a modified Delphi process preferred measures were selected for regular use in most clinic settings.
Results
The search identified 5,199 articles, of which 110 were included in the review. This search identified 46 RA disease activity measures that contained patient, provider, laboratory, and/or imaging data. Descriptions of the measures, properties, study quality, level of evidence, and feasibility were ed and scored. Following a modified Delphi process, 11 measures fulfilled a minimum standard for regular use in most clinic settings, and 5 measures were recommended: the Disease Activity Score in 28 Joints with Erythrocyte Sedimentation Rate or C‐Reactive Protein Level, Clinical Disease Activity Index, Simplified Disease Activity Index, Routine Assessment of Patient Index Data 3, and Patient Activity Scale‐II.
Conclusion
We have updated prior ACR recommendations for preferred RA disease activity measures, identifying 11 measures that met a minimum standard for regular use and 5 measures that were preferred for regular use in most clinic settings.
Objective
To provide guidance on the implementation of recommended American College of Rheumatology (ACR) rheumatoid arthritis (RA) disease activity and functional status assessment measures in ...telehealth settings.
Methods
An expert panel was assembled from the recently convened ACR RA disease activity and functional status measures working groups to summarize strategies for implementation of ACR‐recommended RA disease activity (the Clinical Disease Activity Index CDAI, Disease Activity Score in 28 joints using the erythrocyte sedimentation rate or the C‐reactive protein level DAS28‐ESR/CRP, Patient Activity Scale II PAS‐II, Simplified Disease Activity Index SDAI, and Routine Assessment of Patient Index Data 3 RAPID3) and functional status (the Health Assessment Questionnaire II HAQ‐II, Multidimensional Health Assessment Questionnaire MDHAQ, and PROMIS physical function 10‐item short form PROMIS PF‐10) measures in telehealth settings.
Results
Measures composed of patient‐reported items (disease activity: PAS‐II, RAPID3; functional status: HAQ‐II, MDHAQ, PROMIS PF‐10) require minimal modification for use in telehealth settings. Measures requiring formal joint counts (the CDAI, DAS28‐ESR/CRP, and SDAI) can be calculated using patient‐reported swollen and tender joint counts. When the feasibility of laboratory testing is limited, the CDAI can be used in place of the SDAI, and scoring modifications of the DAS28‐ESR/CRP without the acute‐phase reactant are available. Assessment of the validity of these modifications is limited. Implementation of these measures can be facilitated by electronic health record collection, mobile applications, and provider/staff administration during telehealth visits.
Conclusion
The ACR‐recommended RA disease activity and functional status measures can be adapted for use in telehealth settings to support high‐quality clinical care. Research is needed to better understand how telehealth settings may impact the validity of these measures.
Introduction: The optimal management strategies for patients with polytraumatic injuries that include traumatic brain injury (TBI) are not well defined. Specific interventions including tranexamic ...acid (TXA), propranolol, and hypertonic saline (HTS) have each demonstrated benefits in patient mortality after TBI, but have not been applied to TBI patients with concomitant hemorrhage. The goals of our study were to determine the inflammatory effects of resuscitation strategy using HTS or shed whole blood (WB) and evaluate the cerebral and systemic inflammatory effects of adjunct treatment with TXA and propranolol after combined TBI + hemorrhagic shock. Methods: Mice underwent TBI via weight drop and were subsequently randomized into six experimental groups: three with HTS resuscitation and three with WB resuscitation. Mice were then subjected to controlled hemorrhagic shock for 1 h to a goal MAP of 25 mmHg. Mice were then treated with an i.p. dose of 4 mg/kg propranolol, 100 mg/kg TXA, or normal saline (NS) as a control. Mice were killed at 1, 6, or 24 h for serum and cerebral biomarker evaluation by multiplex ELISA and serum neuron-specific enolase, a biomarker of cerebral cellular injury. Results: Mice resuscitated with HTS had elevated serum proinflammatory cytokines compared with WB resuscitated groups at 6 and 24 h after injury, with no significant difference in cerebral cytokine levels. Within the TBI/shock + HTS groups, the addition of propranolol or TXA did not significantly alter serum cytokine concentration, but cerebral IL-2, IL-12, and macrophage inflammatory protein-1α (MIP-1α) decreased after propranolol administration. In the TBI/shock + WB cohorts, the addition of both propranolol and TXA increased systemic proinflammatory cytokine levels at 6 and 24 h after injury as demonstrated by serum IL-2, IL-12, MIP-1α, and IL-1β compared with NS control. By contrast, TBI/shock + WB mice demonstrated a significant reduction in cerebral IL-2, IL-12, and MIP-1α in propranolol treated mice 6 h after injury compared with NS group. While serum neuron-specific enolase was significantly increased 1 and 24 h after injury in TBI/shock + HTS + TXA cohorts compared with NS control, it was significantly reduced in the TBI/shock + WB + propranolol mice compared with NS control 24 h after injury. Conclusions: Whole blood resuscitation can reduce the acute postinjury neuroinflammatory response after combined TBI/shock compared with HTS. The addition of either propranolol or TXA may modulate the postinjury systemic and cerebral inflammatory response with more improvements noted after propranolol administration. Multimodal treatment with resuscitation and pharmacologic therapy after TBI and hemorrhagic shock may mitigate the inflammatory response to these injuries to improve recovery.
The sepsis syndrome represents an improper immune response to infection and is associated with unacceptably high rates of mortality and morbidity. The interactions between T cells and the innate ...immune system while combating sepsis are poorly understood. In this report, we observed that treatment with the potent, antiapoptotic cytokine interleukin-7 (IL-7) accelerated neutrophil recruitment and improved bacterial clearance. We first determined that T cells were necessary for the previously observed IL-7-mediated enhanced survival. Next, IL-7 increased Bcl-2 expression in T cells isolated from septic mice as early as 3 h following treatment. This treatment resulted in increased gamma interferon (IFN-γ) and IP-10 production within the septic peritoneum together with local and systemic increases of IL-17 in IL-7-treated mice. We further demonstrate that the increase in IL-17 was largely due to increased recruitment and production by γδ T cells, which express CXCR3. Consistent with increased IL-17 production, IL-7 treatment increased CXCL1/KC production, neutrophil recruitment, and bacterial clearance. Significantly, end-organ tissue injury was not significantly different between vehicle- and IL-7-treated mice. Collectively, these data illustrate that IL-7 can mediate the cross talk between Th1 and Th17 lymphocytes during sepsis such that neutrophil recruitment and bacterial clearance is improved while early tissue injury is not increased. All together, these observations may underlay novel potential therapeutic targets to improve the host immune response to sepsis.
Resuscitation with plasma components has been shown to improve endotheliopathy induced by hemorrhagic shock, but the optimal resuscitation strategy to preserve the endothelial glycocalyx has yet to ...be defined. The aim of this study was to determine if resuscitation with lactated Ringer's (LR), whole blood (WB), packed red blood cells (RBCs), platelet-rich plasma (PRP), platelet poor plasma, balanced RBC:PRP (1:1), or day 14 (d14) RBC would best minimize endothelial damage following shock.
Male C57BL/6 mice were hemorrhaged to a goal mean arterial pressure of 25 mm Hg for 1 hour. Unshocked sham mice served as controls. Mice were then resuscitated with equal volumes of LR, WB, RBC, PRP, platelet poor plasma, 1:1, or d14 RBC and then sacrificed at 1, 4, or 24 hours (n = 5). Serum was analyzed for syndecan-1, ubiquitin C-terminal hydrolase L1, and cytokine concentrations. Lungs underwent syndecan-1 immunostaining, and lung injury scores were calculated after hematoxylin and eosin. Proteolytic cleavage of the endothelial glycocalyx was assessed by serum matrix metalloprotease 9 levels.
Serum syndecan-1 and ubiquitin C-terminal hydrolase L1 levels were significantly increased following resuscitation with d14 RBC compared with other groups. Early elevation in lung syndecan-1 staining was noted in LR-treated mice, while d14 mice showed decreased staining compared with sham mice following shock. Lung injury scores were significantly elevated 4 hours after resuscitation with LR and d14 RBC compared with WB. Serum matrix metalloprotease 9 levels were significantly increased at 1 and 4 hours in d14 mice compared with sham mice. Systemic inflammation was increased in animals receiving LR, 1:1, or d14 RBC.
Resuscitation with WB following hemorrhagic shock reduces endothelial syndecan-1 shedding and mitigates lung injury. Aged RBC and LR fail to attenuate endothelial injury following hemorrhagic shock. Further research will be necessary to determine the effect of each of these resuscitative fluids in a hemorrhagic shock model with the addition of tissue injury.
Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) ...inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI.
An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation.
One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS.
Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.
Traumatic brain injury (TBI) can lead to neurocognitive decline, in part due to phosphorylated tau (p-tau). Whether p-tau accumulation worsens in the setting of polytrauma remains unknown. ...Propranolol has shown clinical benefit in head injuries; however, the underlying mechanism is also unknown. We hypothesize that hemorrhagic shock would worsen p-tau accumulation but that propranolol would improve functional outcomes on behavioral studies.
A murine polytrauma model was developed to examine the accumulation of p-tau and whether it can be mitigated by early administration of propranolol. TBI was induced using a weight-drop model and hemorrhagic shock was achieved via controlled hemorrhage for 1 h. Mice were given intraperitoneal propranolol 4 mg/kg or saline control. The animals underwent behavioral testing at 30 d postinjury and were sacrificed for cerebral histological analysis. These studies were completed in male and female mice.
TBI alone led to increased p-tau generation compared to sham on both immunohistochemistry and immunofluorescence (P < 0.05). The addition of hemorrhage led to greater accumulation of p-tau in the hippocampus (P < 0.007). In male mice, p-tau accumulation decreased with propranolol administration for both polytrauma and TBI alone (P < 0.0001). Male mice treated with propranolol also outperformed saline-control mice on the hippocampal-dependent behavioral assessment (P = 0.0013). These results were not replicated in female mice; the addition of hemorrhage did not increase p-tau accumulation and propranolol did not demonstrate a therapeutic effect.
Polytrauma including TBI generates high levels of hippocampal p-tau, but propranolol may help prevent this accumulation to improve both neuropathological and functional outcomes in males.
"Endotheliopathy of trauma" is recognized as endothelial dysfunction following traumatic injury leading to poor patient outcomes. Acute post-traumatic disruptions in endothelial cell function have ...been associated with profound physiologic, hemodynamic, and coagulation derangements. The goal of this study was to define the generation and extent of endotheliopathy in murine polytrauma models by evaluating the post-traumatic release of serum biomarkers of ongoing cellular injury.
Mice were randomized to undergo moderately severe concussive TBI by weight drop, 60-min hemorrhagic shock to MAP 25 mmHg with subsequent resuscitation with Lactated Ringer's, submandibular bleed (SMB), and/or midline laparotomy with rectus muscle crush. Mice were sacrificed at 1, 4, or 24 h for serum biomarker evaluation.
Serum biomarkers revealed differential timing of elevation and injury-dependent release.At 24 h, soluble thrombomodulin was significantly elevated in combined TBI + shock + lap crush compared to untouched, and shock alone. Syndecan-1 levels were significantly elevated after shock 1 to 24 h compared to untouched cohorts with a significant elevation in TBI + shock + lap crush 24 h after injury compared to shock alone. UCHL-1 was significantly elevated in shock mice at 1 to 24 h post-injury compared to untouched mice. UCHL-1 was also significantly elevated in the TBI + shock cohort 24 h after injury compared to shock alone. Hyaluronic acid release at 4 h was significantly elevated in shock alone compared to the untouched cohort with further elevations in TBI + shock + lap crush and TBI + shock compared to shock alone at 24 h. Hyaluronic acid was also increased in lap crush and laparotomy only cohort compared to untouched mice 24 h after injury.
A murine model of polytrauma including TBI, hemorrhagic shock, and laparotomy abdominal crush is a reliable method for evaluation of endotheliopathy secondary to trauma as indicated by differential changes in serum biomarkers.
Leukocyte function can be modulated through the cannabinoid receptor 2 (CB2R). Using a cecal ligation and puncture (CLP) model of sepsis, we examined the role of the CB2R during the immune response ...to an overwhelming infection. CB2R-knock out (KO) mice showed decreased survival as compared with wild-type mice. CB2R-KO mice also had increased serum IL-6 and bacteremia. Twenty-four hours after CLP, the CB2R-deficient mice had increased lung injury. Additionally, CB2R-deficiency led to increased neutrophil recruitment, decreased neutrophil activation, and decreased p38 activity at the site of infection. Consistent with a novel role for CB2R in sepsis, CB2R-agonist treatment in wild-type mice increased the mean survival time in response to CLP. Treatment with CB2R-agonist also decreased serum IL-6 levels, bacteremia, and damage to the lungs compared with vehicle-treated mice. Finally, the CB2R agonist decreased neutrophil recruitment, while increasing neutrophil activation and p38 activity at the site of infection compared with vehicle-treated mice. These data suggest that CB2R is a critical regulator of the immune response to sepsis and may be a novel therapeutic target.
The use of packed red blood cells (pRBCs) for resuscitation is limited by the red blood cell storage lesion, a series of biochemical and physiological changes that occur during the storage and aging ...of blood. Microvesicles (MVs) shed from pRBCs during this process are one component of the red blood cell storage lesion and lead to acute lung injury and pulmonary vascular microthrombi. We hypothesized that MVs from stored pRBCs lead to the release of P-selectin and von Willebrand factor (vWF) from endothelial cells and that this mechanism is mediated via activation of protein kinase C (PKC) or protein kinase A (PKA).
Leukoreduced, platelet-poor murine pRBCs were isolated from C57BL/6 8–12 week-old male mice via cardiac puncture, prepared via centrifugation using a Ficoll gradient, and stored for up to 14 days, the equivalent of 42 days of storage in humans. MVs were isolated from the stored pRBC units via sequential high-speed centrifugation. Murine lung endothelial cells (MLECs) were cultured and grown to confluence, then treated with MVs and either calphostin C, a PKC inhibitor (10 μg/mL), or PKI 14–22 amide, a PKA inhibitor (10 μM). The supernatant was collected after 1 h. P-selectin and vWF A2 concentrations were quantified via ELISA. Immunofluorescent staining for vWF was performed on MLECs. Statistical analysis was performed via unpaired t-test or ANOVA as indicated and reported as mean ± SD. Concentration is reported as pg/mL.
MLECs treated with MVs isolated from stored pRBCs demonstrated increased release of P-selectin and vWF A2 in a dose-dependent fashion. MLECs treated with MVs prepared from stored as compared to fresh pRBCs demonstrated increased release of P-selectin (3751 ± 726 vs 359 ± 64 pg/mL, p < 0.0001) and vWF A2 (3141 ± 355 vs 977 ± 75 pg/mL, p < 0.0001) with increasing duration of storage. The treatment of MVs with calphostin C decreased the amount of P-selectin (1471 ± 444 vs 3751 ± 726 pg/mL, p < 0.0001) and VWF A2 (2401 ± 289 vs 3141 ± 355 pg/mL, p = 0.0017) released into the supernatant by MLECs compared to MVs alone. The treatment of MVs with PKI 14–22 increased the amount of P-selectin released compared to MVs alone (1999 ± 67 vs 1601 ± 135 pg/mL, p = 0.0018).
MVs from stored pRBCs stimulate the release of P-selectin and VWF A2 from endothelial cells. The effect of MVs increases with both dose of MVs and age of stored pRBCs from which they are formed. This mechanism is dependent on activation of PKC and inhibition of this enzyme represents a potentially significant strategy to modulate the inflammatory response to resuscitation with stored pRBCs.
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