Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and ethnic minority populations, the safety and efficacy of the anti-interleukin-6 receptor antibody tocilizumab in patients from these populations who are hospitalized with Covid-19 pneumonia are unclear. METHODS: We randomly assigned (in a 2:1 ratio) patients hospitalized with Covid-19 pneumonia who were not receiving mechanical ventilation to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. Site selection was focused on the inclusion of sites enrolling high-risk and minority populations. The primary outcome was mechanical ventilation or death by day 28. RESULTS: A total of 389 patients underwent randomization, and the modified intention-to-treat population included 249 patients in the tocilizumab group and 128 patients in the placebo group; 56.0% were Hispanic or Latino, 14.9% were Black, 12.7% were American Indian or Alaska Native, 12.7% were non-Hispanic White, and 3.7% were of other or unknown race or ethnic group. The cumulative percentage of patients who had received mechanical ventilation or who had died by day 28 was 12.0% (95% confidence interval [CI], 8.5 to 16.9) in the tocilizumab group and 19.3% (95% CI, 13.3 to 27.4) in the placebo group (hazard ratio for mechanical ventilation or death, 0.56; 95% CI, 0.33 to 0.97; P = 0.04 by the log-rank test). Clinical failure as assessed in a time-to-event analysis favored tocilizumab over placebo (hazard ratio, 0.55; 95% CI, 0.33 to 0.93). Death from any cause by day 28 occurred in 10.4% of the patients in the tocilizumab group and 8.6% of those in the placebo group (weighted difference, 2.0 percentage points; 95% CI, -5.2 to 7.8). In the safety population, serious adverse events occurred in 38 of 250 patients (15.2%) in the tocilizumab group and 25 of 127 patients (19.7%) in the placebo group. CONCLUSIONS: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival. No new safety signals were identified. (Funded by Genentech; EMPACTA ClinicalTrials.gov number, NCT04372186.).

Treatment patterns in US patients hospitalized with COVID-19 and pulmonary involvement.

This study describes the baseline characteristics and treatment patterns of US patients hospitalized with a diagnosis of coronavirus disease 2019 (COVID-19) and pulmonary involvement. Patients hospitalized with pulmonary involvement due to COVID-19 (first hospitalization) were identified in the IBM Explorys® electronic health records database. Demographics, baseline clinical characteristics, and in-hospital medications were assessed. For evaluation of in-hospital medications, results were stratified by race, geographic region, age, and month of admission. Of 6564 hospitalized patients with COVID-19-related pulmonary involvement, 50.4% were male, and mean (SD) age was 62.6 (16.4) years; 75.2% and 23.6% of patients were from the South and Midwest, respectively, and 50.2% of patients were African American. Compared with African American patients, a numerically higher proportion of White patients received dexamethasone (19.7% vs. 31.8%, respectively), nonsteroidal anti-inflammatory drugs (NSAIDs; 27.1% vs. 34.9%), bronchodilators (19.8% vs. 29.5%), and remdesivir (9.3% vs. 21.0%). Numerically higher proportions of White patients than African American patients received select medications in the South but not in the Midwest. Compared with patients in the South, a numerically higher proportion of patients in the Midwest received dexamethasone (20.1% vs. 34.5%, respectively), NSAIDs (19.6% vs. 55.7%), bronchodilators (15.9% vs. 41.3%), and remdesivir (10.6% vs. 23.1%). Inpatient use of hydroxychloroquine decreased over time, whereas the use of dexamethasone and remdesivir increased over time. Among US patients predominantly from the South and Midwest hospitalized with COVID-19 and pulmonary involvement, differences were seen in medication use between different races, geographic regions, and months of hospitalization.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Precision medicine and precision therapeutics: hedgehog signaling pathway, basal cell carcinoma and beyond.

Precision medicine and precision therapeutics is currently in its infancy with tremendous potential to improve patient care by better identifying individuals at risk for skin cancer and predict tumor responses to treatment. This review focuses on the Hedgehog signaling pathway, its critical role in the pathogenesis of basal cell carcinoma, and the emergence of targeted treatments for advanced basal cell carcinoma. Opportunities to utilize precision medicine are outlined, such as molecular profiling to predict basal cell carcinoma response to targeted therapy and to inform therapeutic decisions.

A Review of the Evolving Landscape of Inclusive Research and Improved Clinical Trial Access.

Current clinical research does not reflect the diversity of patient populations, despite continued recommendations to increase enrollment of under-represented racial and ethnic groups. The ramifications of this lack of trial diversity are important because of potential differences between races and ethnicities in response to therapies, which have been observed for drugs across indications. Nonrepresentative research populations limit the generalizability of study results, which may lead to questions about safety and efficacy in certain subgroups of patients and hinder regulators, healthcare providers, and patients in their ability to adequately consider the benefits and risks of a therapeutic treatment across all populations. Renewed efforts to address healthcare disparities and increase diversity in clinical trials have demonstrated that inclusive trials are achievable and can provide scientifically rigorous results, and, thus, should stimulate greater action across all stakeholders. Ensuring that studies throughout the clinical development process include representative populations is a scientific imperative to advance health equity, racial justice, and trust in the safety and efficacy of medical therapies. This article reviews the long-standing lack of diversity and barriers to enrollment of diverse and representative populations in clinical trials, outlines the current evolving trial landscape and the efforts of stakeholders, and provides examples from scientifically rigorous inclusive trials. The goal is to share learnings in a wider context of opportunities to enhance diversity, equity, and inclusion in clinical development while ensuring the safety and efficacy of medical therapies in all populations of patients, and in doing so, provide wider patient access to therapeutic treatments.

Mechanical ventilation for COVID-19: Outcomes following discharge from inpatient treatment.

Though mechanical ventilation (MV) is used to treat patients with severe coronavirus disease 2019 (COVID-19), little is known about the long-term health implications of this treatment. Our objective was to determine the association between MV for treatment of COVID-19 and likelihood of hospital readmission, all-cause mortality, and reason for readmission. This study was a longitudinal observational design with electronic health record (EHR) data collected between 3/1/2020 and 1/31/2021. Participants included 17,652 patients hospitalized for COVID-19 during this period who were followed through 6/30/2021. The primary outcome was readmission to inpatient care following discharge. Secondary outcomes included all-cause mortality and reason for readmission. Rates of readmission and mortality were compared between ventilated and non-ventilated patients using Cox proportional hazards regression models. Differences in reasons for readmission by MV status were compared using multinomial logistic regression. Patient characteristics and measures of illness severity were balanced between those who were mechanically ventilated and those who were not utilizing 1-to-1 propensity score matching. The sample had a median age of 63 and was 47.1% female. There were 1,131 (6.4%) patients who required MV during their initial hospitalization. Rates (32.1% versus 9.9%) and hazard of readmission were greater for patients requiring MV in the propensity score-matched samples [hazard ratio (95% confidence interval) = 3.34 (2.72-4.10)]. Rates (15.3% versus 3.4%) and hazard [hazard ratio (95% confidence interval) = 3.12 (2.32-4.20)] of all-cause mortality were also associated with MV status. Ventilated patients were more likely to be readmitted for reasons which were classified as COVID-19, infectious diseases, and respiratory diagnoses compared to non-ventilated patients. Mechanical ventilation is a necessary treatment for severely ill patients. However, it may be associated with adverse outcomes including hospital readmission and death. More intense post-discharge monitoring may be warranted to decrease this associational finding.

Outcomes during and after long-term tocilizumab treatment in patients with giant cell arteritis.

OBJECTIVE: To assess outcomes in giant cell arteritis (GCA) patients during and after long-term tocilizumab (TCZ) treatment. METHODS: Retrospective analysis of GCA patients treated with TCZ at a single centre (2010-2022). Time to relapse and annualised relapse rate during and after TCZ treatment, prednisone use, and safety were assessed. Relapse was defined as reappearance of any GCA clinical manifestation that required treatment intensification, regardless of C reactive protein levels and erythrocyte sedimentation rate. RESULTS: Sixty-five GCA patients were followed for a mean (SD) of 3.1 (1.6) years. The mean duration of the initial TCZ course was 1.9 (1.1) years. The Kaplan-Meier (KM)-estimated relapse rate at 18 months on TCZ was 15.5%. The first TCZ course was discontinued due to satisfactory remission achievement in 45 (69.2%) patients and adverse events in 6 (9.2%) patients. KM-estimated relapse rate at 18 months after TCZ discontinuation was 47.3%. Compared with patients stopping TCZ at or before 12 months of treatment, the multivariable adjusted HR (95% CI) for relapse in patients on TCZ beyond 12 months was 0.01 (0.00 to 0.28; p=0.005). Thirteen patients received >1 TCZ course. Multivariable adjusted annualised relapse rates (95% CI) in all periods on and off TCZ aggregated were 0.1 (0.1 to 0.2) and 0.4 (0.3 to 0.7), respectively (p=0.0004). Prednisone was discontinued in 76.9% of patients. During the study, 13 serious adverse events occurred in 11 (16.9%) patients. CONCLUSION: Long-term TCZ treatment was associated with remission maintenance in most patients with GCA. The estimated relapse rate by 18 months after TCZ discontinuation was 47.3%.

Treatment Patterns, Disease Burden, and Outcomes in Patients with Giant Cell Arteritis and Polymyalgia Rheumatica: A Real-World, Electronic Health Record-Based Study of Patients in Clinical Practice.

INTRODUCTION: Because of the chronic nature of giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR), patients may require continued glucocorticoid treatment to achieve treatment targets or prevent disease relapse, resulting in high cumulative doses. This study evaluated patterns of glucocorticoid use and outcomes in patients with GCA, PMR, or both. METHODS: This retrospective study used electronic medical records from a US rheumatology clinic utilizing the JointMan® (Discus Analytics, LLC) rheumatology software. Patients aged ≥ 50 years with a diagnosis of GCA or PMR and ≥ 1 entry for a glucocorticoid prescription after diagnosis were included. Outcomes at 2 years after glucocorticoid initiation included the proportion of patients discontinuing glucocorticoids for ≥ 6 months, proportion of patients discontinuing glucocorticoids for ≥ 6 months and remaining off glucocorticoids at 2 years, time to discontinuation of glucocorticoids for ≥ 6 months, and prednisone dose and were compared between patients with GCA only, PMR only, or GCA and PMR. RESULTS: At 2 years after the initiation of glucocorticoids, 32% of patients (26/91) with GCA, 32% (248/779) with PMR, and 27% (26/97) with GCA and PMR discontinued glucocorticoids for ≥ 6 months; 17, 23, and 18% discontinued glucocorticoids for ≥ 6 months and remained off glucocorticoids at 2 years, respectively. Median (range) time to discontinuation of glucocorticoids for ≥ 6 months was 202.5 (0-635) days and shorter in patients with both GCA and PMR vs. GCA or PMR only. The majority of patients required daily prednisone at 2 years, with similar doses observed between groups. CONCLUSIONS: Fewer than one-third of patients with GCA and/or PMR discontinued glucocorticoids for ≥ 6 months; the majority of patients required prednisone therapy for ≥ 2 years after its initiation. These data highlight the need for the use of more efficacious and glucocorticoid-sparing therapies in patients with GCA and/or PMR.

Baseline Demographics and Clinical Characteristics Among 3471 US Patients Hospitalized with COVID-19 and Pulmonary Involvement: A Retrospective Study.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) can present as a range of symptoms, from mild to critical; lower pulmonary involvement, including pneumonia, is often associated with severe and critical cases. Understanding the baseline characteristics of patients hospitalized with COVID-19 illness is essential for effectively targeting clinical care and allocating resources. This study aimed to describe baseline demographics and clinical characteristics of US patients hospitalized with COVID-19 and pulmonary involvement. METHODS: US patients with COVID-19 and pulmonary involvement during an inpatient admission from December 1, 2019, to May 20, 2020, were identified using the IBM Explorys® electronic health records database. Baseline (up to 12 months prior to first COVID-19 hospitalization) demographics and clinical characteristics and preadmission (14 days to 1 day prior to admission) pulmonary diagnoses were assessed. Patients were stratified by sex, age, race, and geographic region. RESULTS: Overall, 3471 US patients hospitalized with COVID-19 and pulmonary involvement were included. The mean (SD) age was 63.5 (16.3) years; 51.2% of patients were female, 55.0% African American, 81.6% from the South, and 16.8% from the Midwest. The most common comorbidities included hypertension (27.7%), diabetes (17.3%), hyperlipidemia (16.3%), and obesity (9.7%). Cough (27.3%) and dyspnea (15.2%) were the most common preadmission pulmonary symptoms. African American patients were younger (mean [SD], 62.5 [15.4] vs. 67.8 [6.2]) with higher mean (SD) body mass index (33.66 [9.46] vs. 30.42 [7.86]) and prevalence of diabetes (19.8% vs. 16.7%) and lower prevalence of chronic obstructive pulmonary disease (5.6% vs. 8.2%) and smoking/tobacco use (28.1% vs. 37.2%) than White patients. CONCLUSIONS: Among US patients primarily from the South and Midwest hospitalized with COVID-19 and pulmonary involvement, the most common comorbidities were hypertension, diabetes, hyperlipidemia, and obesity. Differences observed between African American and White patients should be considered in the context of the complex factors underlying racial disparities in COVID-19.

Adverse Events in Giant Cell Arteritis and Rheumatoid Arthritis Patient Populations: Analyses of Tocilizumab Clinical Trials and Claims Data.

INTRODUCTION: The safety profile of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) is well established. TCZ was approved to treat giant cell arteritis (GCA) in 2017 in the USA and Europe, and its safety profile in patients with GCA continues to be defined. The objective of this analysis was to examine incidence rates (IRs) of adverse events of special interest (AESI) occurring during the TCZ clinical development program and in healthcare claims data in patients with GCA or RA. METHODS: TCZ-naïve patients with GCA or RA were identified in the MarketScan administrative healthcare claims database. TCZ-treated patients with GCA from the GiACTA trial and TCZ-treated patients with RA from pooled clinical trial data were analyzed. The IRs of AESI (AESI IRs) were calculated for all cohorts. In the claims cohorts, risks of AESI were estimated using Poisson regression. RESULTS: TCZ-naïve claims cohorts comprised 4804 patients with GCA [mean (standard deviation) age 73.4 (9.8) years; follow-up 3.9 (3.1) years] and 15,164 patients with RA [age 60.3 (8.2) years; follow-up, 4.5 (2.8) years]. TCZ-treated clinical trial cohorts comprised 149 patients with GCA [age 69.5 (8.4) years; exposure approx. 138 patient-years (PY)] and 7647 with RA [age 52 (12.6) years; exposure approx. 22,394 PY]. The IRs of infections, stroke, malignancies, myocardial infarction, and gastrointestinal perforations in the GCA claims cohort exceeded those in the RA claims cohort; the risk of AESI (adjusted for age and glucocorticoid use) was higher in patients with GCA than in those with RA. Similar patterns to the claims cohorts in terms of the AESI IRs were observed in clinical trial cohorts, although the number of events was limited in the GCA trial cohort. CONCLUSION: Higher IRs of AESI were observed in patients with GCA versus those with RA in both TCZ-naïve and -treated cohorts. Differences in underlying disease, age, and glucocorticoid use may influence AESI incidence, irrespective of intervention. FUNDING: This study was funded by F. Hoffmann-La Roche Ltd and Genentech, Inc. Article processing charges were funded by F. Hoffmann-La Roche Ltd. Plain language summary is available for this article.

Risk Associated with Cumulative Oral Glucocorticoid Use in Patients with Giant Cell Arteritis in Real-World Databases from the USA and UK.

INTRODUCTION: Treatment of giant cell arteritis (GCA) involves immediate initiation of high-dose glucocorticoid therapy with slow tapering of the dose over many months. Chronic exposure to glucocorticoids is associated with serious comorbidities. The objective of this analysis was to determine the glucocorticoid exposure and risk of glucocorticoid-related adverse events (AEs) in real-world patients with GCA. METHODS: Data from the Truven Healthcare MarketScan® database (from January 1, 2000, to June 30, 2015) and the Clinical Practice Research Datalink (CPRD; from January 1, 1995, to August 31, 2013) were used to retrospectively analyze patients aged ≥ 50 years with GCA in the USA and UK, respectively. Outcomes included oral glucocorticoid use (cumulative prednisone-equivalent exposure), glucocorticoid-related AEs and the association of AE risk with glucocorticoid exposure over 52 weeks. RESULTS: Of the 4804 patients in the US MarketScan database and 3973 patients in the UK CPRD database included, 71.3 and 74.6% were women and mean age was 73.4 and 73.0 years, respectively. Median starting glucocorticoid dose and cumulative glucocorticoid dose at 52 weeks were 20-50 mg/day and 4000-4800 mg, respectively. The most frequent glucocorticoid-related AEs were hypertension and eye, bone health, and glucose tolerance conditions. In the first year after diagnosis, the likelihood of any glucocorticoid-related AE was significantly increased for each 1 g increase in cumulative glucocorticoid dose in the US and UK cohorts (odds ratio [95% CI], 1.170 [1.063, 1.287] and 1.06 [1.03, 1.09], respectively; P < 0.05 for both). Similar trends were observed for the risk of glucocorticoid-related AEs over full follow-up (mean, USA: 3.9 years, UK: 6.3 years). CONCLUSIONS: In real-world patients with GCA, increased cumulative glucocorticoid exposure was associated with an increased risk of glucocorticoid-related AEs. FUNDING: F. Hoffmann-La Roche Ltd. Plain language summary available for this article.

Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma.

IMPORTANCE: Smoothened inhibitors (SIs) are a new type of targeted therapy for advanced basal cell carcinoma (BCC), and their long-term effects, such as increased risk of subsequent malignancy, are still being explored. OBJECTIVE: To evaluate the risk of developing a non-BCC malignancy after SI exposure in patients with BCC. DESIGN, SETTING, AND PARTICIPANTS: A case-control study at Stanford Medical Center, an academic hospital. Participants were higher-risk patients with BCC diagnosed from January 1, 1998, to December 31, 2014. The dates of the analysis were January 1 to November 1, 2015. EXPOSURES: The exposed participants (cases) comprised patients who had confirmed prior vismodegib treatment, and the nonexposed participants (controls) comprised patients who had never received any SI. Because vismodegib was the first approved SI, only patients exposed to this SI were included. MAIN OUTCOMES AND MEASURES: Hazard ratio for non-BCC malignancies after vismodegib exposure, adjusting for covariates. RESULTS: The study cohort comprised 180 participants. Their mean (SD) age at BCC diagnosis was 56 (16) years, and 68.9% (n = 124) were male. Fifty-five cases were compared with 125 controls, accounting for age, sex, prior radiation therapy or cisplatin treatment, Charlson Comorbidity Index, clinical follow-up time, immunosuppression, and basal cell nevus syndrome status. Patients exposed to vismodegib had a hazard ratio of 6.37 (95% CI, 3.39-11.96; P < .001), indicating increased risk of developing a non-BCC malignancy. Most non-BCC malignancies were cutaneous squamous cell carcinomas, with a hazard ratio of 8.12 (95% CI, 3.89-16.97; P < .001), accounting for age and basal cell nevus syndrome status. There was no significant increase in other cancers. CONCLUSIONS AND RELEVANCE: Increased risk for cutaneous squamous cell carcinomas after vismodegib therapy highlights the importance of continued skin surveillance after initiation of this therapy.

Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma.

Smoothened inhibitors represent the first class of targeted drugs approved for use in advanced and metastatic basal cell carcinoma. For many patients with limited treatment options, this drug class has led to significant clinical improvements, but is not without side effects. In this review, we outline the basic mechanism of smoothened inhibitors and the most commonly observed cutaneous and extracutaneous side effects. We also highlight possible mechanisms for these adverse events and current management strategies.

Advanced Basal Cell Carcinoma: Epidemiology and Therapeutic Innovations.

Advanced basal cell carcinomas are a subset of basal cell carcinomas that can be difficult to treat either due to their local invasiveness, proximity to vital structures, or metastasis. The incidence of all basal cell carcinoma is increasing in the United States, although it is not known whether advanced basal cell carcinomas (aBCCs) are also increasing. Recently, highly targeted therapy based on knowledge of the basal cell carcinoma pathogenesis has become available either commercially or through human clinical trials. These orally available drugs inhibit the Hedgehog signaling pathway, and lead to advanced basal cell carcinoma shrinkage that can enable preservation of adjacent vital organs. In this review, we outline the role of Hedgehog pathway inhibitors as well as other treatment modalities such as excision, radiotherapy and more traditional chemotherapy in treating advanced basal cell carcinomas. We also highlight current gaps in knowledge regarding the use and side effects of this targeted therapy.

Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells.

In the HLA class II-associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.

Giant cell arteritis: immune and vascular aging as disease risk factors.

Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.