Self-reported determinants of COVID-19 vaccine acceptance among persons with and without autoimmune disease.

OBJECTIVE: Patients with autoimmune disease (AD) are at increased risk for complications from COVID-19 infection, so, optimizing vaccine utilization in this population is of particular importance. We compared COVID-19 vaccination perspectives among persons with and without AD. METHODS: 471 patients in the MetroHealth System and Cleveland Veteran Affairs Medical Center completed a 38-item questionnaire between August 2021 and February 2022. This survey containing questions regarding COVID-19 vaccine perceptions and demographics was administered both to unvaccinated individuals and individuals who delayed vaccination for at least 2 months. Multivariable ordinary least squares regression models were created to assess factors associated with vaccination likelihood. RESULTS: The number of reasons given for (p < 0.001) and against receiving COVID-19 vaccination (p < 0.001) were highly associated with increased and decreased vaccination likelihood respectively. Factors most closely associated with obtaining vaccine were: protecting family (p = 0.045) personal safety (p < 0.001) and preventing serious infection (p < 0.001). Reasons associated with decreased vaccination likelihood were: lack of concern of COVID-19 infection (p < 0.001), vaccine safety (p < 0.001) and beliefs that the vaccine was made too quickly (p = 0.024). AD patients were more likely to cite having a chronic condition (29.1 % vs 17.1 %, p = 0.003) and physician recommendation(s) (18.4 % vs 9.1 %, p = 0.005) as reasons for vaccination and were more concerned about potential medication interaction than non-AD respondents (22.4 % vs 3.3 %, p < 0.001). CONCLUSION: The number of benefits of vaccination identified strongly related to vaccination likelihood. Affirmative provider recommendations correlated with increased vaccination likelihood in AD patients. Clinical conversations centered on the benefits of COVID-19 vaccination may help increase vaccine acceptance.

Higher Vitamin D Levels before Methotrexate Therapy Initiation Are Associated with Lower Subsequent Mortality in Patients with Rheumatoid Arthritis.

(1) Vitamin D deficiency is associated with mortality in the general population and has been observed in one rheumatoid arthritis (RA) cohort. Here, we investigate the relationship between 25-hydroxyvitamin D (25(OH)D) levels before methotrexate (MTX) therapy initiation in patients with RA and the subsequent all-cause mortality in a national Veterans Affairs (VA) cohort. (2) This is a retrospective study on RA patients time-oriented around the initial MTX prescription and 25(OH)D levels before starting MTX. We examined survival in patients with 25(OH)D levels > 50 nmol/L and ≤50 nmol/L using the Cox Proportional Hazard Model and fully adjusted for risk factors. (3) In total, 15,109 RA patients were included in the nationwide cohort. RA patients with 25(OH)D levels > 50 nmol/L before starting MTX had a 28% reduced risk of mortality when compared to those with levels ≤ 50 nmol/L (HR: 0.72, CI: 0.64-0.80, p < 0.001) after adjusting for traditional risk factors. (4) In this national RA cohort receiving standard-of-care MTX, patients with 25(OH)D levels > 50 nmol/L have a lower subsequent mortality when compared to those with 25(OH)D levels ≤ 50 nmol/L. It remains to be determined whether increasing Vitamin D levels in RA patients initially found to be Vitamin D deficient impacts their all-cause mortality.

New-onset autoimmune disease after COVID-19.

Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may trigger autoimmune disease (AD) through initial innate immune activation with subsequent aberrations in adaptive immune cells leading to AD. While there are multiple reports of incident AD diagnosed after COVID-19, the risk in the context of key circulating strains is unknown. Methods: TriNetX, a global, federated, health research network providing access to electronic medical records across 74 healthcare organizations, was utilized to define an adult cohort between January 1, 2020, and March 3, 2023. Exposure was defined as COVID-19 diagnosis (ICD-10 code or positive laboratory test). Age- and sex-propensity score-matched controls never had COVID-19 diagnosed. Outcomes were assessed 1 month to 1 year after the index date. Patients with AD prior to or within 1 month after the index date were excluded from the primary analysis. Incidence and risk ratios of each AD were assessed. Results: A total of 3,908,592 patients were included. Of 24 AD patients assessed, adjusted risk ratios for eight AD patients who had COVID-19 were higher compared to those who had no COVID-19. Cutaneous vasculitis (adjusted hazard ratio (aHR): 1.82; 95% CI 1.55-2.13), polyarteritis nodosa (aHR: 1.76; 95% CI 1.15-2.70), and hypersensitivity angiitis (aHR: 1.64; 95% CI 1.12-2.38) had the highest risk ratios. Overall, psoriasis (0.15%), rheumatoid arthritis (0.14%), and type 1 diabetes (0.13%) had the highest incidence during the study period, and of these, psoriasis and diabetes were more likely after COVID-19. The risk of any AD was lower if COVID-19 was diagnosed when Omicron variants were the predominant circulating strains. A positive antinuclear antibody was more likely and predictive of AD after COVID-19. Discussion: SARS-CoV-2 may be a potential trigger for some AD, but the risk for AD may decrease with time given the apparent lower risk after infection with Omicron variants.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Financial Incentives Are Associated with Lower Likelihood of COVID-19 Vaccination in Northeast Ohio.

BACKGROUND: Declining COVID-19 vaccination rates have led to implementation of monetary incentives to increase vaccine uptake. The Ohio Vax-a-Million lottery and subsequent $100 incentives were created to encourage individuals to become vaccinated. The purpose of this survey was to determine the efficacy of these monetary incentives on vaccination rates. METHODS: A 38-item questionnaire was given to outpatients at MetroHealth and Cleveland Veteran Affairs Hospitals between August 2021 and February 2022 who either waited 2 or more months to receive the COVID-19 vaccination or have not yet been vaccinated. The survey contained questions regarding demographics and perceptions of COVID-19 monetary incentives on vaccination likelihood. RESULTS: Of the 471 participants surveyed, 0.95% reported that the Ohio Vax-a-Million lottery increased their vaccination likelihood, while 29.7% reported that it decreased their likelihood. 6.8% of respondents reported the $100 incentive increased their vaccination likelihood while 17.4% reported it decreased their vaccination chances. 20.6% of participants stated news of the Delta (δ) variant increased their vaccination likelihood. CONCLUSION: Our study results suggest that monetary incentives were not associated with increased COVID-19 vaccination rates. Instead, more participants believed that these incentives decreased their vaccination likelihood. Expansion of the survey across a wider sociodemographic range can provide further evidence of the efficacy of these programs before reimplementation.

Optimization of Human Mesenchymal Stem Cells for Rheumatoid Arthritis: Implications for Improved Therapeutic Outcomes.

OBJECTIVE: Seropositive rheumatoid arthritis (RA) is a chronic autoimmune disease that is rarely "cured." Human mesenchymal stem cells (hMSCs) are known to reduce inflammation and restore immune homeostasis. However, methods for predicting therapeutic hMSC potency have not been established. The goal of these studies was to use and refine an ex vivo functional assay that determines potency of hMSCs and can then be validated in clinical trials as a potency measure of hMSCs used therapeutically to treat RA. METHODS: Allogeneic hMSCs were cytokine-stimulated, and a conditioned medium (CM) was harvested. The CM was tested for the potential to attenuate RA CD4+ T cell proliferation using suppression assays. Indoleamine 2, 3-dioxygenase (IDO) mRNA, and protein were quantified in hMSCs as a measure to compare hMSCs across (prior) studies. RESULTS: To mimic a proinflammatory environment that resembles that in RA, interleukin-1(IL1ß), tumor necrosis factor α (TNFα), and interferon γ (IFNγ) (alone or in combination) were used to precondition hMSCs. Treating hMSCs with a combination of these cytokines generated a CM "secretome" that suppressed T cell proliferation between 70 and 83%. Forty-eight hours of cytokine preconditioning hMSCs was required to maximize this effect. T cell suppression positively correlated with increases in hMSC cellular IDO mRNA and protein. CONCLUSION: By standardizing assays to measure hMSC effects, their potency on T cell suppression can be quantified. These studies demonstrate that hMSCs can be compared functionally to identify optimal preparation(s) for therapeutic use in RA and that the potency of hMSC-dependent T cell suppression may differ between hMSC donors. Clinical studies are warranted to validate the hypothesis that ex vivo potency in suppressing T cells will positively correlate with a reduction in RA disease activity and increase in immunological quiescence.

CDCP1 on Dendritic Cells Contributes to the Development of a Model of Kawasaki Disease.

The etiology and pathology of Kawasaki disease (KD) remain elusive. Cub domain-containing protein 1 (CDCP1), a cell-surface protein that confers poor prognosis of patients with certain solid tumors, was recently identified as one of the most significantly upregulated genes in SARS-CoV-2-infected children who developed systemic vasculitis, a hallmark of KD. However, a potential role of CDCP1 in KD has not previously been explored. In this study, we found that CDCP1 knockout (KO) mice exhibited attenuated coronary and aortic vasculitis and decreased serum Candida albicans water-soluble fraction (CAWS)-specific IgM/IgG2a and IL-6 concentrations compared with wild-type mice in an established model of KD induced by CAWS administration. CDCP1 expression was not detectable in cardiomyocytes, cardio fibroblasts, or coronary endothelium, but constitutive expression of CDCP1 was observed on dendritic cells (DCs) and was upregulated by CAWS stimulation. CAWS-induced IL-6 production was significantly reduced in CDCP1 KO DCs, in association with impaired Syk-MAPK signaling pathway activation. These novel findings suggest that CDCP1 might regulate KD development by modulating IL-6 production from DCs via the Syk-MAPK signaling pathway.

Prioritizing studies of COVID-19 and lessons learned.

INTRODUCTION: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research. METHODS: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data. RESULTS: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization. CONCLUSIONS: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics.

Differences in Healthcare Transition Views, Practices, and Barriers Among North American Pediatric Rheumatology Clinicians From 2010 to 2018.

OBJECTIVE: Since 2010, the rheumatology community has developed guidelines and tools to improve healthcare transition. In this study, we aimed to compare current transition practices and beliefs among Childhood Arthritis and Rheumatology Research Alliance (CARRA) rheumatology providers with transition practices from a provider survey published in 2010. METHODS: In 2018, CARRA members completed a 25-item online survey about healthcare transition. Got Transition's Current Assessment of Health Care Transition Activities was used to measure clinical transition processes on a scale of 1 (basic) to 4 (comprehensive). Bivariate analyses were used to compare 2010 and 2018 survey findings. RESULTS: Over half of CARRA members completed the survey (202/396), including pediatric rheumatologists, adult- and pediatric-trained rheumatologists, pediatric rheumatology fellows, and advanced practice providers. The most common target age to begin transition planning was 15-17 years (49%). Most providers transferred patients prior to age 21 years (75%). Few providers used the American College of Rheumatology transition tools (31%) or have a dedicated transition clinic (23%). Only 17% had a transition policy in place, and 63% did not consistently address healthcare transition with patients. When compared to the 2010 survey, improvement was noted in 3 of 12 transition barriers: availability of adult primary care providers, availability of adult rheumatologists, and pediatric staff transition knowledge and skills (P < 0.001 for each). Nevertheless, the mean current assessment score was < 2 for each measurement. CONCLUSION: This study demonstrates improvement in certain transition barriers and practices since 2010, although implementation of structured transition processes remains inconsistent.

CD6 is a target for cancer immunotherapy.

Limitations of checkpoint inhibitor cancer immunotherapy include induction of autoimmune syndromes and resistance of many cancers. Since CD318, a novel CD6 ligand, is associated with the aggressiveness and metastatic potential of human cancers, we tested the effect of an anti-CD6 monoclonal antibody, UMCD6, on killing of cancer cells by human lymphocytes. UMCD6 augmented killing of breast, lung, and prostate cancer cells through direct effects on both CD8+ T cells and NK cells, increasing cancer cell death and lowering cancer cell survival in vitro more robustly than monoclonal antibody checkpoint inhibitors that interrupt the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) axis. UMCD6 also augmented in vivo killing by human peripheral blood lymphocytes of a human breast cancer line xenotransplanted into immunodeficient mice. Mechanistically, UMCD6 upregulated the expression of the activating receptor NKG2D and downregulated expression of the inhibitory receptor NKG2A on both NK cells and CD8+ T cells, with concurrent increases in perforin and granzyme B production. The combined capability of an anti-CD6 monoclonal antibody to control autoimmunity through effects on CD4+ lymphocyte differentiation while enhancing killing of cancer cells through distinct effects on CD8+ and NK cells opens a potential new approach to cancer immunotherapy that would suppress rather than instigate autoimmunity.

Attenuation of Murine Collagen-Induced Arthritis by Targeting CD6.

OBJECTIVE: CD6 is an important regulator of T cell function that interacts with the ligands CD166 and CD318. To further clarify the significance of CD6 in rheumatoid arthritis (RA), we examined the effects of targeting CD6 in the mouse model of collagen-induced arthritis (CIA), using CD6-knockout (CD6-KO) mice and CD6-humanized mice that express human CD6 in lieu of mouse CD6 on their T cells. METHODS: We immunized wild-type (WT) and CD6 gene-KO mice with a collagen emulsion to induce CIA. For treatment studies using CD6-humanized mice, mice were immunized similarly and a mouse anti-human CD6 IgG (UMCD6) or control IgG was injected on days 7, 14, and 21. Joint tissues were evaluated for tissue damage, leukocyte infiltration, and local inflammatory cytokine production. Collagen-specific Th1, Th9, and Th17 responses and serum levels of collagen-specific IgG subclasses were also evaluated in WT and CD6-KO mice with CIA. RESULTS: The absence of CD6 reduced 1) collagen-specific Th9 and Th17, but not Th1 responses, 2) the levels of many proinflammatory joint cytokines, and 3) serum levels of collagen-reactive total IgG and IgG1, but not IgG2a and IgG3. Joint homogenate hemoglobin content was significantly reduced in CD6-KO mice with CIA compared to WT mice with CIA (P < 0.05) (reduced angiogenesis). Moreover, treating CD6-humanized mice with mouse anti-human CD6 monoclonal antibody was similarly effective in reducing joint inflammation in CIA. CONCLUSION: Taken together, these data suggest that interaction of CD6 with its ligands is important for the perpetuation of CIA and other inflammatory arthritides that are T cell driven.

Challenges to Practicing Pediatric Rheumatology.

Pediatric rheumatology is an exciting and rewarding career area. However, challenges when attracting trainees to this field include practice often occurring in smaller groups compared with general pediatrics, available positions requiring relocation, and fluctuation in funding resulting in uncertainty regarding training positions. Having critical mass in pediatric divisions is important to ensure adequate mentoring and people power to produce scholarly work, reduce on-call frequency and mitigate faculty absences that result in unplanned addition of clinical work. Compensation has historically lagged behind that of general pediatrics. Increased research opportunities through organized networks, patient and parent engagement, and the increasing recognition of pediatric rheumatologists as contributing to scholarship has heightened the profile of pediatric rheumatology nationally and internationally.

Sustained Response Following Discontinuation of Methotrexate in Patients With Rheumatoid Arthritis Treated With Subcutaneous Tocilizumab: Results From a Randomized, Controlled Trial.

OBJECTIVE: To evaluate whether tocilizumab (TCZ) monotherapy is noninferior to treatment with TCZ plus methotrexate (MTX) for maintaining clinical responses in patients with rheumatoid arthritis (RA) in whom low disease activity is achieved with TCZ plus MTX. METHODS: Patients with RA who experienced an inadequate response to MTX received MTX plus TCZ 162 mg subcutaneously. At 24 weeks, patients who achieved a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) of ≤3.2 were randomized to receive TCZ monotherapy or to continue treatment with TCZ plus MTX until week 52. The primary outcome measure was the comparison of the mean change in the DAS28-ESR from week 24 to week 40 between the TCZ monotherapy and TCZ plus MTX arms (noninferiority margin of 0.6). Secondary outcome measures included worsening of the DAS28-ESR by ≥1.2, achievement of a DAS28-ESR of <2.6 and ≤3.2, and safety and immunogenicity. RESULTS: Among the 718 patients enrolled, 296 were randomized at week 24 to receive TCZ monotherapy (n = 147) or TCZ plus MTX (n = 147). The mean changes in the DAS28-ESR from week 24 to week 40 were 0.46 and 0.14 in the TCZ monotherapy arm and the TCZ plus MTX arm, respectively (weighted difference between the groups, 0.318 [95% confidence interval 0.045, 0.592]); discontinuing MTX in TCZ responders was noninferior to continuing MTX. Safety events were broadly similar between the randomized treatment groups; the most common serious adverse event was infection, which occurred in 2.1% of patients in the TCZ monotherapy group and 2.2% of patients receiving TCZ plus MTX. CONCLUSION: Patients with RA receiving TCZ plus MTX who achieve low disease activity can discontinue MTX without significant worsening of disease activity during the 16 weeks following MTX discontinuation.

CD318 is a ligand for CD6.

It has been proposed that CD6, an important regulator of T cells, functions by interacting with its currently identified ligand, CD166, but studies performed during the treatment of autoimmune conditions suggest that the CD6-CD166 interaction might not account for important functions of CD6 in autoimmune diseases. The antigen recognized by mAb 3A11 has been proposed as a new CD6 ligand distinct from CD166, yet the identity of it is hitherto unknown. We have identified this CD6 ligand as CD318, a cell surface protein previously found to be present on various epithelial cells and many tumor cells. We found that, like CD6 knockout (KO) mice, CD318 KO mice are also protected in experimental autoimmune encephalomyelitis. In humans, we found that CD318 is highly expressed in synovial tissues and participates in CD6-dependent adhesion of T cells to synovial fibroblasts. In addition, soluble CD318 is chemoattractive to T cells and levels of soluble CD318 are selectively and significantly elevated in the synovial fluid from patients with rheumatoid arthritis and juvenile inflammatory arthritis. These results establish CD318 as a ligand of CD6 and a potential target for the diagnosis and treatment of autoimmune diseases such as multiple sclerosis and inflammatory arthritis.

CD6 as a potential target for treating multiple sclerosis.

CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell-driven autoimmune conditions.

CD6 Receptor Regulates Intestinal Ischemia/Reperfusion-induced Injury by Modulating Natural IgM-producing B1a Cell Self-renewal.

Intestinal ischemia/reperfusion (I/R) injury is a relatively common pathological condition that can lead to multi-organ failure and mortality. Regulatory mechanism for this disease is poorly understood, although it is established that circulating pathogenic natural IgM, which is primarily produced by B1a cells outside of the peritoneal cavity, are integrally involved. CD6 was originally identified as a marker for T cells and was later found to be present on some subsets of B cells in humans; however, whether CD6 plays any role in intestinal I/R-induced injury and, if so, the underlying mechanisms, remain unknown. Here we report that CD6-/- mice were significantly protected from intestinal inflammation and mucosal damage compared with WT mice in a model of intestinal I/R-induced injury. Mechanistically, we found that CD6 was selectively expressed on B1 cells outside of the bone marrow and peritoneal cavity and that pathogenic natural IgM titers were reduced in the CD6-/- mice in association with significantly decreased B1a cell population. Our results reveal an unexpected role of CD6 in the pathogenesis of intestinal IR-induced injury by regulating the self-renewal of B1a cells.

Development of a Functional Biomarker for Use in Cell-Based Therapy Studies in Seropositive Rheumatoid Arthritis.

UNLABELLED: Cell-based therapy has potential therapeutic value in autoimmune diseases such as rheumatoid arthritis (RA). In RA, reduction of disease activity has been associated with improvement in the function of regulatory T cells (Treg) and attenuated responses of proinflammatory effector T cells (Teff). Mesenchymal stem cells (MSCs) and related multipotent adult progenitor cells (MAPC) have strong anti-inflammatory and immunomodulatory properties and may be able to "reset" the immune system to a pre-RA state. MAPC are MSC-like cells that are slightly earlier in lineage, have greater expansion capacity, and can be used as "off-the-shelf" therapy. Assessment of cell-based therapy to treat arthritis and related diseases is limited by the lack of available biological correlates that can be measured early on and indicate treatment response. We set out to develop a functional measure that could be used ex vivo as a biomarker of response. We were able to demonstrate that MAPC products could inhibit Teff responses from patients with active RA and that Treg from RA patients suppressed Teff. This assay used ex vivo can be used with MAPC or Treg alone or in combination and reflects the overall level of Teff suppression. Use of a novel functional biomarker as an exploratory endpoint in trials of cell-based therapy should be of value to detect biological outcomes at a point prior to the time that clinical response might be observed. SIGNIFICANCE: Therapy with mesenchymal stem cells and related multipotent adult progenitor cells is immune modifying in a variety of diseases. There is interest in using cell-based therapy in rheumatoid arthritis (RA) to induce tolerance and "reset" the immune system to its pre-RA state. In a clinical trial, it should be known as soon as possible if there is a chance of response. A biomarker has been developed that permits measurement of the effects of cell-based therapy on effector T cell function.

A Point-of-Care Raman Spectroscopy-Based Device for the Diagnosis of Gout and Pseudogout: Comparison With the Clinical Standard Microscopy.

OBJECTIVE: To demonstrate the usefulness of a novel medical device based on Raman spectroscopy for the rapid point-of-care diagnosis of gout and pseudogout. METHODS: A shoebox-sized point-of-care Raman spectroscopy (POCRS) device was developed for use in the diagnosis of gout and pseudogout. The device included a disposable syringe microfiltration kit to collect arthropathic crystals from synovial fluid and a customized automated Raman spectroscopy system to chemically identify crystal species. Diagnosis according to the findings of POCRS was compared with the clinical standard diagnosis based on compensated polarized light microscopy (CPLM) of synovial fluid aspirates collected from symptomatic patients (n = 174). Kappa coefficients were used to measure the agreement between POCRS and CPLM findings. RESULTS: Overall, POCRS and CPLM results were consistent in 89.7% of samples (156 of 174). For the diagnosis of gout, the kappa coefficient for POCRS and CPLM was 0.84 (95% confidence interval [95% CI] 0.75-0.94). For the diagnosis of pseudogout, the kappa coefficient for POCRS and CPLM was 0.61 (95% CI 0.42-0.81). CONCLUSION: Kappa coefficients indicated that there was excellent agreement between POCRS and CPLM for the diagnosis of gout, with good agreement for the diagnosis of pseudogout. The POCRS device holds the potential to standardize and expedite the time to clinical diagnosis of gout and pseudogout, especially in settings where certified operators trained for CPLM analysis are not available.

Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults.

OBJECTIVE: Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity. METHODS: We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH-AI) and the tubulointerstitial activity index (TIAI). High LN-activity status (versus moderate/low) was defined as NIH-AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN-activity status for both NIH-AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN-activity status was determined. RESULTS: The differential excretion of 6 UBMs (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN-activity (NIH-AI) status with >92% accuracy and LN-activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN-activity status was confirmed by principal component and linear discriminant analyses. CONCLUSION: The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.