Update on gout management: what is old and what is new.

PURPOSE OF REVIEW: The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality and societal costs. In this review, we discuss recent advances in epidemiology and treatment strategies for gout. RECENT FINDINGS: Genetic factors and obesity are prominent contributors to hyperuricemia and gout, while dietary factors contribute to less variance in serum urate, though can still have some contribution to population attributable risk. A consensus statement by the Gout, Hyperuricemia and Crystal-Associated Disease Network outlined appropriate terminology regarding gout, which will aid in communication about various aspects of the disease. The 2020 American College of Rheumatology gout guideline offers comprehensive evidence-based recommendations for the management of hyperuricemia using urate-lowering therapy, prophylaxis when initiating urate-lowering therapy, treatment of gout flare and adjunctive management strategies. There is improved understanding of risk factors for allopurinol hypersensitivity syndrome and well tolerated use of allopurinol in chronic kidney disease. Trial data have provided new insights regarding cardiovascular risk with febuxostat. Several new drug therapies are being tested for both urate-lowering efficacy and gout flare management. SUMMARY: Although there have been significant advances in understanding of risk factors and treatment approaches, gout remains suboptimally managed. There is substantial need for improving gout management efforts and gout education among patients and clinicians.

Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

A distinct association of inflammatory molecules with outcomes of COVID-19 in younger versus older adults.

Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.

Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease.

In Gaucher disease, several macrophage-specific biomarkers have been validated for use in the clinic. However, Gaucher disease is more complex involving system-wide pathophysiology beyond the macrophage, and based on gene array analysis in our Gaucher disease mouse model and other emerging pathophysiologic insights, we evaluated serum levels of cathepsins D and S, YKL-40 and progranulin in Gaucher disease patients. We assessed their biomarker potential in Gaucher disease and compared them to established Gaucher disease biomarkers, chitotriosidase, chemokine ligand 18 (CCL18), and other indicators of disease severity and response to therapy. Mean YKL-40 and cathepsin D and S levels were significantly higher in Gaucher disease patients compared to healthy controls; in contrast, mean progranulin levels were lower in Gaucher disease patients compared to healthy controls. Enzyme replacement therapy resulted in a significant reversal of elevated cathepsin D and S but there was no change in progranulin and YKL-40 levels. Patients with persistent splenomegaly after long-term enzyme replacement therapy had significantly higher serum YKL-40 than patients with smaller spleens (63.0 ±â€¯6.4 ng/ml vs. 46.4 ±â€¯4.3 ng/ml, p = .03). Serum YKL-40 levels were higher in subjects with severe bone involvement (Hermann Score 3 to 5) compared to those with milder bone involvement (Hermann Score 1 to 2) (70.1 ±â€¯4.3 ng/ml vs. 48.1 ±â€¯3.7 ng/ml, p = .0002). YKL-40 was only weakly associated with chitotriosidase (r = 0.2, p = .008) and CCL18 (r = 0.3, p = .0004), and cathepsin S was moderately associated with chitotriosidase (r = 0.4, p = .01) and CCL18 (r = 0.6, p < .0001). Receiver operating curves for progranulin and YKL-40 demonstrated areas under the curves of 0.80 and 0.70, respectively. In conclusion, while these biomarkers do not meet robust properties of established macrophage-specific biomarkers, they may inform severity of skeletal disease, contribution of fibrosis to residual splenomegaly, and other disease manifestations. These findings, including markedly low progranulin levels that do not change upon enzyme replacement therapy, are intriguing to prompt further investigations to decipher their role in pathophysiology and relevance to diverse phenotypes of Gaucher disease.

Use of Wireless Capsule Endoscopy for the Diagnosis and Grading of Esophageal Varices in Patients With Portal Hypertension: A Systematic Review and Meta-Analysis.

INTRODUCTION: Esophageal variceal bleeding is a severe complication of portal hypertension with significant morbidity and mortality. Although traditional screening and grading of esophageal varices has been performed by endogastroduodenoscopy (EGD), wireless video capsule endoscopy provides a minimally invasive alternative that may improve screening and surveillance compliance. AIM OF THE STUDY: The aim of the study was to perform a systematic review and structured meta-analysis of all eligible studies to evaluate the efficacy of wireless capsule endoscopy for screening and diagnosis of esophageal varices among patients with portal hypertension. METHODS: Searches of PubMed, EMBASE, Web of Science, and the Cochrane Library databases were performed through December 2015. Bivariate and hierarchical models were used to compute the pooled sensitivity and specificity, and to plot the summary receiver operating characteristics curve with summary point and corresponding 95% confidence region. Bias of included studies was assessed using the quality assessment of diagnostic accuracy studies-2. RESULTS: Seventeen studies from 2005 to 2015 were included in this meta-analysis (n=1328). The diagnostic accuracy of wireless capsule endoscopy in the diagnosis of esophageal varices was 90% [95% confidence interval (CI), 0.88-0.93]. The diagnostic pooled sensitivity and specificity were 83% (95% CI, 0.76-0.89) and 85% (95% CI, 0.75-0.91), respectively. The diagnostic accuracy of wireless capsule endoscopy for the grading of medium to large varices was 92% (95% CI, 0.90-0.94). The pooled sensitivity and specificity were 72% (95% CI, 0.54-0.85) and 91% (95% CI, 0.86-0.94), respectively, for the grading of medium to large varices. The use of capsule demonstrated only mild adverse events. A sensitivity analysis limited to only high quality studies revealed similar results. DISCUSSION: Wireless esophageal capsule endoscopy is well tolerated and safe in patients with liver cirrhosis and suspicion of portal hypertension. The sensitivity of capsule endoscopy is not currently sufficient to replace EGD as a first exploration in these patients, but given its high accuracy, it may have a role in cases of refusal or contraindication to EGD.

IL-1 receptor 1 signaling shapes the development of viral antigen-specific CD4+ T cell responses following COVID-19 mRNA vaccination.

BACKGROUND: The innate immune cytokine interleukin (IL)-1 can affect T cell immunity, a critical factor in host defense. In a previous study, we identified a subset of human CD4+ T cells which express IL-1 receptor 1 (IL-1R1). However, the expression of such receptor by viral antigen-specific CD4+ T cells and its biological implication remain largely unexplored. This led us to investigate the implication of IL-1R1 in the development of viral antigen-specific CD4+ T cell responses in humans, including healthy individuals and patients with primary antibody deficiency (PAD), and animals. METHODS: We characterized CD4+ T cells specific for SARS-CoV-2 spike (S) protein, influenza virus, and cytomegalovirus utilizing multiplexed single cell RNA-seq, mass cytometry and flow cytometry followed by an animal study. FINDINGS: In healthy individuals, CD4+ T cells specific for viral antigens, including S protein, highly expressed IL-1R1. IL-1ß promoted interferon (IFN)-γ expression by S protein-stimulated CD4+ T cells, supporting the functional implication of IL-1R1. Following the 2nd dose of COVID-19 mRNA vaccines, S protein-specific CD4+ T cells with high levels of IL-1R1 increased, likely reflecting repetitive antigenic stimulation. The expression levels of IL-1R1 by such cells correlated with the development of serum anti-S protein IgG antibody. A similar finding of increased expression of IL-1R1 by S protein-specific CD4+ T cells was also observed in patients with PAD following COVID-19 mRNA vaccination although the expression levels of IL-1R1 by such cells did not correlate with the levels of serum anti-S protein IgG antibody. In mice immunized with COVID-19 mRNA vaccine, neutralizing IL-1R1 decreased IFN-γ expression by S protein-specific CD4+ T cells and the development of anti-S protein IgG antibody. INTERPRETATION: Our results demonstrate the significance of IL-1R1 expression in CD4+ T cells for the development of viral antigen-specific CD4+ T cell responses, contributing to humoral immunity. This provides an insight into the regulation of adaptive immune responses to viruses via the IL-1 and IL-1R1 interface. FUNDING: Moderna to HJP, National Institutes of Health (NIH) 1R01AG056728 and R01AG055362 to IK and KL2 TR001862 to JJS, Quest Diagnostics to IK and RB, and the Mathers Foundation to RB.

Segmental isotope labeling of proteins for NMR structural study using a protein S tag for higher expression and solubility.

A common obstacle to NMR studies of proteins is sample preparation. In many cases, proteins targeted for NMR studies are poorly expressed and/or expressed in insoluble forms. Here, we describe a novel approach to overcome these problems. In the protein S tag-intein (PSTI) technology, two tandem 92-residue N-terminal domains of protein S (PrS(2)) from Myxococcus xanthus is fused at the N-terminal end of a protein to enhance its expression and solubility. Using intein technology, the isotope-labeled PrS(2)-tag is replaced with non-isotope labeled PrS(2)-tag, silencing the NMR signals from PrS(2)-tag in isotope-filtered (1)H-detected NMR experiments. This method was applied to the E. coli ribosome binding factor A (RbfA), which aggregates and precipitates in the absence of a solubilization tag unless the C-terminal 25-residue segment is deleted (RbfAΔ25). Using the PrS(2)-tag, full-length well-behaved RbfA samples could be successfully prepared for NMR studies. PrS(2) (non-labeled)-tagged RbfA (isotope-labeled) was produced with the use of the intein approach. The well-resolved TROSY-HSQC spectrum of full-length PrS(2)-tagged RbfA superimposes with the TROSY-HSQC spectrum of RbfAΔ25, indicating that PrS(2)-tag does not affect the structure of the protein to which it is fused. Using a smaller PrS-tag, consisting of a single N-terminal domain of protein S, triple resonance experiments were performed, and most of the backbone (1)H, (15)N and (13)C resonance assignments for full-length E. coli RbfA were determined. Analysis of these chemical shift data with the Chemical Shift Index and heteronuclear (1)H-(15)N NOE measurements reveal the dynamic nature of the C-terminal segment of the full-length RbfA protein, which could not be inferred using the truncated RbfAΔ25 construct. CS-Rosetta calculations also demonstrate that the core structure of full-length RbfA is similar to that of the RbfAΔ25 construct.

Concurrent use of tumor necrosis factor inhibitor and tyrosine kinase inhibitor in ankylosing spondylitis and myeloid neoplasm.

Biologic disease-modifying agents (bDMARDs) are highly effective in controlling the symptoms of autoimmune rheumatic diseases. The decision on whether to continue bDMARDs following a cancer diagnosis can be challenging for patients and physicians. Here, we describe a case of a middle-aged male with ankylosing spondylitis who was controlled on infliximab (IFX) and found to have a myeloid neoplasm with Platelet-Derived Growth Factor Receptor Beta rearrangement. The patient was started on a tyrosine kinase inhibitor imatinib. Given its significant positive effect on patient's quality of life, IFX was continued with a favorable outcome. This case highlights the importance of shared decisionmaking in balancing risks and benefits of immunosuppressants in appropriate cases of hematologic malignancy.

Community Private Practice Clinical Experience with Peanut Oral Immunotherapy.

BACKGROUND: Peanut oral immunotherapy is an effective treatment for desensitizing peanut-allergic patients, but the frequency of adverse reactions has limited its widespread use. OBJECTIVE: To review the frequency of adverse reactions that patients on peanut oral immunotherapy experience during build-up and maintenance phases and explore factors that may contribute to adverse events. METHODS: A retrospective chart review of children and adults with peanut allergy undergoing peanut oral immunotherapy at the New England Food Allergy Treatment Center in West Hartford, Conn was performed. Data on patient demographics, allergic profile, peanut allergy testing, and details of reactions in build-up and maintenance phases were collected. A systemic reaction was defined as one of the following: (1) severe reaction involving 1 system, such as generalized hives and/or angioedema; (2) 2 or more of the following symptoms: cutaneous or oral, respiratory, or gastrointestinal symptoms; (3) drop in blood pressure; or (4) need for epinephrine. RESULTS: Data were available on 783 patients aged 3.5 to 48.3 years. During buildup, 78 patients (10%) experienced at least 1 systemic reaction, 660 (84%) at least 1 gastrointestinal adverse event, 369 (47%) at least 1 cutaneous adverse event, and 157 (20%) at least 1 respiratory adverse event. Thirty-four patients (4%) required epinephrine during buildup. Six hundred ninety-seven patients (89%) completed buildup and progressed to maintenance. During maintenance, 131 patients (19%) experienced at least 1 systemic reaction, 190 (27%) at least 1 gastrointestinal adverse event, 104 (15%) at least 1 cutaneous adverse event, and 50 (7%) at least 1 respiratory adverse event. Seventy-four patients (11%) required epinephrine during maintenance. None of the adverse events required hospitalizations, and there were no mortalities. Nine patients (1%) were diagnosed with eosinophilic esophagitis during buildup or maintenance. Increasing pretreatment peanut specific IgE levels were associated with increased odds of a systemic reaction during buildup. Increasing age, pretreatment peanut specific IgE level, and a systemic reaction in buildup were associated with increased odds of a systemic reaction during maintenance. CONCLUSIONS: Peanut oral immunotherapy may be an effective and safe treatment for carefully selected peanut-allergic patients under the guidance of experienced providers. Specific patient characteristics and immunologic factors may help predict adverse events.

Low Fasting Oxytocin Levels Are Associated With Psychopathology in Anorexia Nervosa in Partial Recovery.

OBJECTIVE: Anorexia nervosa (AN), a psychiatric disorder characterized by restriction of food intake despite severe weight loss, is associated with increased comorbid anxiety and depression. Secretion of oxytocin, an appetite-regulating neurohormone with anxiolytic and antidepressant properties, is abnormal in AN. The link between oxytocin levels and psychopathology in AN has not been well explored. METHODS: We performed a cross-sectional study of 79 women aged 18-45 years (19 AN, 26 AN in partial recovery [ANPR], and 34 healthy controls [HC]) investigating the relationship between basal oxytocin levels and disordered eating psychopathology, anxiety, and depressive symptoms. AN diagnoses were based on DSM-5 criteria. Data acquisition took place between December 2008 and March 2014. Fasting serum oxytocin levels were obtained, and the following self-report measures were used to assess psychopathology: Eating Disorder Examination Questionnaire, State-Trait Anxiety Inventory, and Beck Depression Inventory-II. RESULTS: Fasting oxytocin levels were low in ANPR compared to HC (P = .0004). In ANPR but not AN, oxytocin was negatively associated with disordered eating psychopathology (r = -0.39, P = .0496) and anxiety symptoms (state anxiety: r = -0.53, P = .006; trait anxiety: r = -0.49, P = .01). Furthermore, ANPR with significant disordered eating psychopathology, anxiety symptoms, or depressive symptoms had lower oxytocin levels compared to those with minimal or no symptoms (P = .04, .02, and .007, respectively). CONCLUSIONS: We speculate that a dysregulation of oxytocin pathways may contribute to persistent psychopathology after partial weight recovery from anorexia nervosa.

The efficacy and safety profile of albumin administration for patients with cirrhosis at high risk of hepatorenal syndrome is dose dependent.

BACKGROUND: Albumin is a critical component in the standard therapeutic approach to acute renal failure (ARF) and spontaneous bacterial peritonitis (SBP) in the setting of ascites. However, data regarding the safety and minimum effective dose are limited. METHODS: We conducted a retrospective review of patients with decompensated cirrhosis who received albumin within the first 48 hours of hospitalization at Beth Israel Deaconess Medical Center between 2010 and 2013. Outcomes included 90-day risk of death or transplantation (primary) and (secondary) complications of albumin infusion (length of stay (LOS) and need for critical care)), all adjusted for comorbidity and severity of illness. RESULTS: We included 169 patients with ARF and 88 patients with SBP. The optimal doses of albumin for a survival benefit were found to be 87.5 g and 100 g in the ARF and SBP cohorts, respectively. The odds ratio (OR) for the 90-day risk of death or liver transplantation associated with the optimal loading dose was 0.36 (95% CI: 0.17-0.76, P = 0.008) and 0.28 (95% CI: 0.07-0.97, P = 0.04) for the ARF and SBP cohorts, respectively. This effect persisted for patients with ARF who had neither hepatorenal syndrome (HRS) nor SBP (OR: 0.13, 95% CI: 0.007-0.79, P = 0.02). LOS (beta coefficient per log albumin dose: 1.69; 95% CI: 0.14-3.24, P = 0.03) and risk of critical care (OR/g albumin: 1.03; 95% CI: 1.01-1.05, P = 0.01) were also dose dependent. CONCLUSION: Albumin has a dose-dependent effect on both survival and complications in patients with cirrhosis with ARF (HRS and otherwise) and/or SBP.