Opportunistic Infections, Mortality Risk, and Prevention Strategies in Patients With Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective.

Skin Manifestations of VEXAS Syndrome and Associated Genotypes.

Importance: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations. Objective: To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features. Design, Setting, and Participants: This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland. Main Outcomes and Measures: To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS. Results: Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]). Conclusions and Relevance: Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.

Health disparities in systemic lupus erythematosus-a narrative review.

PURPOSE OF REVIEW: To describe root causes of health disparities by reviewing studies on incidence and outcomes of systemic lupus erythematosus (SLE) related to ethnic, race, gender, or socioeconomic differences and to propose solutions. RECENT FINDINGS: SLE outcomes have steadily improved over the past 40 years but are not uniformly distributed across various racial and ethnic groups. Belonging to racial and ethnic minority has been cited as a risk factor for more severe disease and poor outcome in SLE. Population-based registries have demonstrated that Black patients with SLE have significantly lower life expectancy compared to White patients. Lower socioeconomic status has been shown to be one of the strongest predictors of progression to end stage renal disease in lupus nephritis. An association between patient experiences of racial discrimination, increased SLE activity, and damage has also been described. The lack of representation of marginalized communities in lupus clinical trials further perpetuates these disparities. To that end, the goal of a rheumatology workforce that resembles the patients it treats has emerged as one of many solutions to current shortfalls in care. Disparities in SLE incidence, treatment, and outcomes have now been well established. The root causes of these disparities are multifactorial including genetic, epigenetic, and socioeconomic. The underrepresentation of marginalized communities in lupus clinical trials further worsen these disparities. Efforts have been made recently to address disparities in a more comprehensive manner, but systemic causes of disparities must be acknowledged and political will is required for a sustained positive change.

Risk Factors for COVID-19 and Rheumatic Disease Flare in a US Cohort of Latino Patients.

OBJECTIVE: Latino patients are overrepresented among cases of coronavirus disease 2019 (COVID-19) and are at an increased risk of severe disease. Prevalence of COVID-19 in Latinos with rheumatic diseases is poorly reported. This study was undertaken to characterize COVID-19 clinical features and outcomes in Latino patients with rheumatic diseases. METHODS: We conducted a retrospective study of Latino patients with rheumatic diseases from an existing observational cohort in the Washington, DC area. Patients seen between April 1, 2020 and October 15, 2020 were analyzed in this study. We reviewed demographic characteristics, body mass index (BMI), comorbidities, and use of immunomodulatory therapies. An exploratory classification and regression tree (CART) analysis along with logistic regression analyses were performed to identify risk factors for COVID-19 and rheumatic disease flare. RESULTS: Of 178 Latino patients with rheumatic diseases, 32 (18%) were identified as having COVID-19, and the incidence rate of infection was found to be 3-fold higher than in the general Latino population. No patients required intensive care unit-level care. A CART analysis and multivariable logistic regression analysis identified a BMI of >30.35 as a risk factor for COVID-19 (odds ratio [OR] 3.37 [95% confidence interval (95% CI) 1.5-7.7]; P = 0.004). COVID-19 positivity was a risk factor for rheumatic disease flare (OR 4.57 [95% CI 1.2-17.4]; P = 0.02). CONCLUSION: Our findings indicate that Latino patients with rheumatic diseases have a higher rate of COVID-19 compared with the general Latino population. Obesity is a risk factor for COVID-19, and COVID-19 is a risk factor for rheumatic disease flare. Latino patients with risk factors should be closely followed up, especially post-COVID-19 in anticipation of disease flare.

Association of lipoprotein subfractions and glycoprotein acetylation with coronary plaque burden in SLE.

OBJECTIVE: Subjects with SLE display an enhanced risk of atherosclerotic cardiovascular disease (CVD) that is not explained by Framingham risk. This study sought to investigate the utility of nuclear MR (NMR) spectroscopy measurements of serum lipoprotein particle counts and size and glycoprotein acetylation (GlycA) burden to predict coronary atherosclerosis in SLE. METHODS: Coronary plaque burden was assessed in SLE subjects and healthy controls using coronary CT angiography. Lipoproteins and GlycA were quantified by NMR spectroscopy. RESULTS: SLE subjects displayed statistically significant decreases in high-density lipoprotein (HDL) particle counts and increased very low-density lipoprotein (VLDL) particle counts compared with controls. Non-calcified coronary plaque burden (NCB) negatively associated with HDL subsets whereas it positively associated with VLDL particle counts in multivariate adjusted models. GlycA was significantly increased in SLE sera compared with controls. In contrast to high-sensitivity C reactive protein, elevations in GlycA in SLE significantly associated with NCB and insulin resistance (IR), though the association with NCB was no longer significant after adjusting for prednisone use. CONCLUSIONS: Patients with SLE display a proatherogenic lipoprotein profile that may significantly contribute to the development of premature CVD. The results demonstrate that NMR measures of GlycA and lipoprotein profiles, beyond what is captured in routine clinical labs, could be a useful tool in assessing CVD risk in patients with SLE.

Safety and Tolerability of Omalizumab: A Randomized Clinical Trial of Humanized Anti-IgE Monoclonal Antibody in Systemic Lupus Erythematosus.

OBJECTIVE: Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. METHODS: Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction. RESULTS: Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052). CONCLUSION: Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.

Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with enhanced risk of atherosclerotic cardiovascular disease not explained by Framingham risk score (FRS). Immune dysregulation associated to a distinct subset of lupus proinflammatory neutrophils (low density granulocytes; LDGs) may play key roles in conferring enhanced CV risk. This study assessed if lupus LDGs are associated with in vivo vascular dysfunction and inflammation and coronary plaque. METHODS: SLE subjects and healthy controls underwent multimodal phenotyping of vascular disease by quantifying vascular inflammation (18F-fluorodeoxyglucose-PET/CT [18F-FDG-PET/CT]), arterial dysfunction (EndoPAT and cardio-ankle vascular index), and coronary plaque burden (coronary CT angiography). LDGs were quantified by flow cytometry. Cholesterol efflux capacity was measured in high-density lipoprotein-exposed (HDL-exposed) radioactively labeled cell lines. Whole blood RNA sequencing was performed to assess associations between transcriptomic profiles and vascular phenotype. RESULTS: Vascular inflammation, arterial stiffness, and noncalcified plaque burden (NCB) were increased in SLE compared with controls even after adjustment for traditional risk factors. In SLE, NCB directly associated with LDGs and associated negatively with cholesterol efflux capacity in fully adjusted models. A neutrophil gene signature reflective of the most upregulated genes in lupus LDGs associated with vascular inflammation and NCB. CONCLUSION: Individuals with SLE demonstrate vascular inflammation, arterial dysfunction, and NCB, which may explain the higher reported risk for acute coronary syndromes. The association of LDGs and neutrophil genes with vascular disease supports the hypothesis that distinct neutrophil subsets contribute to vascular damage and unstable coronary plaque in SLE. Results also support previous observations that neutrophils may disrupt HDL function and thereby promote atherogenesis. TRIAL REGISTRATION: Clinicaltrials.gov NCT00001372FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute.

A pilot study of yoga as self-care for arthritis in minority communities.

BACKGROUND: While arthritis is the most common cause of disability, non-Hispanic blacks and Hispanics experience worse arthritis impact despite having the same or lower prevalence of arthritis compared to non-Hispanic whites. People with arthritis who exercise regularly have less pain, more energy, and improved sleep, yet arthritis is one of the most common reasons for limiting physical activity. Mind-body interventions, such as yoga, that teach stress management along with physical activity may be well suited for investigation in both osteoarthritis and rheumatoid arthritis. Yoga users are predominantly white, female, and college educated. There are few studies that examine yoga in minority populations; none address arthritis. This paper presents a study protocol examining the feasibility and acceptability of providing yoga to an urban, minority population with arthritis. METHODS/DESIGN: In this ongoing pilot study, a convenience sample of 20 minority adults diagnosed with either osteoarthritis or rheumatoid arthritis undergo an 8-week program of yoga classes. It is believed that by attending yoga classes designed for patients with arthritis, with racially concordant instructors; acceptability of yoga as an adjunct to standard arthritis treatment and self-care will be enhanced. Self-care is defined as adopting behaviors that improve physical and mental well-being. This concept is quantified through collecting patient-reported outcome measures related to spiritual growth, health responsibility, interpersonal relations, and stress management. Additional measures collected during this study include: physical function, anxiety/depression, fatigue, sleep disturbance, social roles, and pain; as well as baseline demographic and clinical data. Field notes, quantitative and qualitative data regarding feasibility and acceptability are also collected. Acceptability is determined by response/retention rates, positive qualitative data, and continuing yoga practice after three months. DISCUSSION: There are a number of challenges in recruiting and retaining participants from a community clinic serving minority populations. Adopting behaviors that improve well-being and quality of life include those that integrate mental health (mind) and physical health (body). Few studies have examined offering integrative modalities to this population. This pilot was undertaken to quantify measures of feasibility and acceptability that will be useful when evaluating future plans for expanding the study of yoga in urban, minority populations with arthritis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01617421.