Impaired innate and adaptive immune responses to BNT162b2 SARS-CoV-2 vaccination in systemic lupus erythematosus.

Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.

OMERACT 2023 Systemic Lupus Erythematosus Special Interest Group: Winnowing and Binning Preliminary Candidate Domains for the Core Outcome Set.

BACKGROUND: The Outcome Measures in Rheumatology (OMERACT) Systemic Lupus Erythematosus (SLE) Working Group held a Special Interest Group (SIG) at the OMERACT 2023 conference in Colorado Springs where SLE collaborators reviewed domain sub-themes generated through qualitative research and literature review. OBJECTIVE: The objective of the SIG and the subsequent meetings of the SLE Working Group was to begin the winnowing and binning of candidate domain sub-themes into a preliminary list of candidate domains that will proceed to the consensus Delphi exercise for the SLE COS. METHODS: Four breakout groups at the SLE SIG in Colorado Springs winnowed and binned 132 domain sub-themes into candidate domains, which was continued with a series of virtual meetings by an advisory group of SLE patient research partners (PRPs), members of the OMERACT SLE Working Group Steering Committee, and other collaborators. RESULTS: The 132 domain sub-themes were reduced to a preliminary list of 20 candidate domains based on their clinical and research relevance for clinical trials and research studies. CONCLUSION: A meaningful and substantial winnowing and binning of candidate domains for the SLE COS was achieved resulting in a preliminary list of 20 candidate domains.

Hydroxychloroquine in Lupus Pregnancy and Risk of Preeclampsia.

OBJECTIVE: Systemic lupus erythematosus (SLE) disproportionately affects women during childbearing years, and hydroxychloroquine (HCQ) is the standard first-line treatment. Preeclampsia complicates up to one-third of pregnancies in lupus patients, although reports vary by parity and multifetal gestation. We investigated whether taking HCQ early in pregnancy may reduce the risk of preeclampsia. METHODS: We studied 1,068 live birth singleton pregnancies among 1,020 privately insured patients with SLE (2007-2016). HCQ treatment was defined as three months preconception through the first trimester, and prescription fills were a proxy for taking HCQ. Modified Poisson regression estimated risk ratios (RRs) and 95% confidence intervals (CIs), stratified by parity. Propensity scores accounted for confounders, and stratified analyses examined effect modification. RESULTS: Approximately 15% of pregnant patients were diagnosed with preeclampsia. In 52% of pregnancies, patients had one or more HCQ fills. Pregnant patients exposed to HCQ had more comorbidities, SLE activity, and azathioprine treatment. We found no evidence of a statistical association between HCQ and preeclampsia among nulliparous (RR 1.26 [95% CI 0.82-1.93]) and multiparous pregnancies (RR 1.20 [95% CI 0.80-1.70]). Additional controls for confounding decreased the RRs toward the null (nulliparous pregnancy, propensity score-adjusted [PS-adj] RR 1.09 [95% CI 0.68-1.76]; multiparous pregnancy, PS-adj RR 1.01 [95% CI 0.66-1.53]). CONCLUSION: Using a large insurance-based database, we did not observe a decreased risk of preeclampsia associated with HCQ treatment in pregnancy, although we cannot rule out residual and unmeasured confounding and misclassification. Further studies leveraging large population-based data and prospective collection could characterize how HCQ influences preeclampsia risk in pregnant patients with SLE and among persons at greater risk of hypertensive disorders of pregnancy.

The Problem of Pain in Rheumatology: Variations in Case Definitions Derived From Chronic Pain Phenotyping Algorithms Using Electronic Health Records.

OBJECTIVE: The aim of this study was to investigate and compare different case definitions for chronic pain to provide estimates of possible misclassification when researchers are limited by available electronic health record and administrative claims data, allowing for greater precision in case definitions. METHODS: We compared the prevalence of different case definitions for chronic pain (N = 3042) in patients with autoimmune rheumatic diseases. We estimated the prevalence of chronic pain based on 15 unique combinations of pain scores, diagnostic codes, analgesic medications, and pain interventions. RESULTS: Chronic pain prevalence was lowest in unimodal pain phenotyping algorithms: 15% using analgesic medications, 18% using pain scores, 21% using pain diagnostic codes, and 22% using pain interventions. In comparison, the prevalence using a well-validated phenotyping algorithm was 37%. The prevalence of chronic pain also increased with the increasing number (bimodal to quadrimodal) of phenotyping algorithms that comprised the multimodal phenotyping algorithms. The highest estimated chronic pain prevalence (47%) was the multimodal phenotyping algorithm that combined pain scores, diagnostic codes, analgesic medications, and pain interventions. However, this quadrimodal phenotyping algorithm yielded a 10% overestimation of chronic pain compared to the well-validated algorithm. CONCLUSION: This is the first empirical study to our knowledge that shows that established common modes of phenotyping chronic pain can lead to substantially varying estimates of the number of patients with chronic pain. These findings can be a reference for biases in case definitions for chronic pain and could be used to estimate the extent of possible misclassifications or corrections in using datasets that cannot include specific data elements.

The Problem of Pain in Rheumatology: Clinical Profiles Associated With Concomitant Diagnoses With Chronic Overlapping Pain Conditions.

OBJECTIVE: The chronification of pain is heterogeneous in rheumatology. Chronic overlapping pain conditions (COPCs) such as fibromyalgia, endometriosis, migraine, and back pain may co-occur with one another and in rheumatic diseases. We describe the sociodemographic and clinical profiles associated with concomitant COPCs among patients with rheumatic diseases. METHODS: We retrospectively identified patients visiting rheumatology clinics at a single institution from 2010 to 2020 for five common rheumatic conditions: psoriatic arthritis (PsA), rheumatoid arthritis (RA), Sjögren syndrome (SjS), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). We compared sociodemographic, clinical, and lifestyle factors by rheumatic condition and by COPC status. We also report sex-stratified diagnosis of COPCs. The primary outcome was diagnostic validation of one or more COPCs. RESULTS: We identified 5992 rheumatology patients: 846 with PsA, 2605 with RA, 956 with SjS, 975 with SLE, and 610 with SSc. Approximately 36-62% of patients had a concomitant COPC diagnosis. Patients with SjS had the highest prevalence (62%). Diagnosis of one or more COPCs was highest among Black patients and lowest among Asian patients. Patients using public insurance had a higher prevalence of one or more COPCs compared with those with private insurance. Patients with one or more COPCs had more depression and anxiety and more frequent emergency department visits, surgeries, and hospitalizations. CONCLUSION: Our findings suggest that COPCs are strikingly common among patients with rheumatic disease and are associated with lower quality of life and greater health care needs. Future research may elucidate drivers of chronic pain and how to best address the unique analgesic needs of this multimorbid population.

Innovative Trials and New Opportunities in SLE.

Despite progress in the treatment of systemic lupus erythematosus (SLE), remission rates and health-related quality of life remain disappointingly low. The paucity of successful SLE clinical trials reminds us that we still have a long way to go. Nevertheless, there are clear signs of hope. We highlight results from recent studies of novel therapeutic strategies based on emerging insights into our understanding of SLE disease mechanisms. We also highlight several studies that inform optimal use of existing treatments to improve efficacy and/or limit toxicity. These developments suggest we may yet unlock the key toward more satisfactory treatment outcomes in SLE.

Pulse dose steroid experience among hospitalized patients with systemic lupus erythematosus: a single-center feasibility study.

INTRODUCTION/OBJECTIVES: Pulse intravenous (IV) methylprednisolone (MEP) is often used for severe SLE manifestations requiring hospitalization. However, the accuracy of pulse dose documentation extracted from the electronic health record (EHR) is unknown. We assessed the feasibility to study pulse steroid dosing among hospitalized patients with SLE at our institution. METHOD:  Using the Stanford Medicine Research Data Repository (STARR) extracted from the EHR, we identified patients with ≥ 1 SLE ICD code before/during hospitalization receiving steroids (1/2008-12/2017). SLE diagnosis required rheumatologist confirmation. For our feasibility study, we randomly sampled 40/747 patients meeting search criteria. Pulse IV MEP was defined as ≥ 200 mg. Pharmacy dispensation data required EHR confirmation. RESULTS:  Forty adult and pediatric subjects were identified, passing initial criteria screen; 6 pediatric patients were excluded as EHR pharmacy confirmation was unavailable. Of the 34 adults, 14 had SLE confirmed. Among 5 adult SLE patients with pulse documentation, 3 occurred while hospitalized, for the following indications: acute renal transplant rejection (2 patients, 2 hospitalizations) and lupus flare (1 patient, 2 hospitalizations). No discrepancies were observed in pharmacy dispensation documentation of pulse dosing between EHR and STARR for all 4 hospitalizations. CONCLUSIONS: Assessment of pulse steroid dose dispensation among hospitalized patients with SLE can be reliably ascertained from the extracted portion of the EHR designed for research. Reliance on a single ICD code for SLE in the EHR may lead to high rate of false-positive diagnoses of SLE among hospitalized patients. We document the importance of supplementing one ICD code with additional clinical information when confirming SLE diagnosis. Key Points • Assessment of pulse steroid dosing dispensation among hospitalized patients with SLE can be reliably determined from the extracted portion of the EHR designed for research purposes. • Reliance on a single ICD code contributes to a high rate of false positive diagnoses of SLE among hospitalized patients. • Supplementing ICD coding with additional clinical information is vital when confirming SLE diagnosis.

Interferon-directed therapies for the treatment of systemic lupus erythematosus: a critical update.

The interferon (IFN) pathway, especially type I IFN, plays a critical role in the immunopathogenesis of systemic lupus erythematosus (SLE). We have gained significant insights into this pathway over the past two decades, including a better understanding of the key mediators of inflammation upstream and downstream of type I IFN. This has led to the identification of multiple potential targets for the treatment of SLE, for which a significant unmet need remains due to the failure of many patients to adequately respond to standard-of-care medications. Unfortunately, most new therapies in SLE have disappointed in preclinical or clinical trials to date, including a number that target type I IFN. Nevertheless, several IFN-directed therapies aimed at specific steps within this immunologic pathway have recently shown promise, and additional agents are in the treatment pipeline. In this review, we focus on the results of key therapeutic studies targeting the type I IFN pathway and discuss the future state of IFN-blockade in SLE.

Phase II, randomised, double-blind, multicentre study evaluating the safety and efficacy of filgotinib and lanraplenib in patients with lupus membranous nephropathy.

OBJECTIVES: Patients with lupus membranous nephropathy (LMN) are at risk for prolonged proteinuria and progressive chronic kidney disease. There are no proven effective treatments for LMN, and controlled trials are lacking. This trial assessed the preferential Janus kinase 1 (JAK1) inhibitor filgotinib and the spleen tyrosine kinase inhibitor lanraplenib in patients with LMN. METHODS: This was a phase II, randomised, double-blind trial conducted at 15 centres in the USA to evaluate the safety and efficacy of filgotinib or lanraplenib for the treatment of LMN. Eligible patients were randomised 1:1 to receive either filgotinib or lanraplenib in a blinded fashion for up to 52 weeks. The primary endpoint was the per cent change in 24-hour urine protein from baseline to week 16. RESULTS: Nine patients were randomised to receive filgotinib (n=5) or lanraplenib (n=4). Four patients in the filgotinib group and one patient in the lanraplenib group completed week 16. There was a median reduction of 50.7% in 24-hour urine protein after 16 weeks of treatment with filgotinib (n=4), and the median Systemic Lupus Erythematosus Disease Activity Index from the Safety of Estrogens in Lupus National Assessment score remained stable. Filgotinib treatment was well tolerated. Limited conclusions can be drawn about treatment with lanraplenib. CONCLUSION: The number of patients treated in this study was small, and only limited conclusions can be drawn. There may be a therapeutic benefit with filgotinib treatment, which may support future investigations with filgotinib or other JAK inhibitors in patients with LMN. TRIAL REGISTRATION NUMBER: NCT03285711.

Increasing Ancestral Diversity in Lupus Trials: Ways Forward.

Significant disparities exist in systemic lupus erythematosus (SLE) regarding prevalence, disease severity, and mortality, with race/ethnic minorities being disproportionately affected in the United States. This review highlights that despite these disparities, race/ethnic minority underrepresentation remains an issue within SLE research. Decreased race/ethnic minority involvement in SLE research has real-world implications, including less understanding of the disease and less applicability of approved therapies among diverse groups of patients. Members of the SLE research community have an obligation to narrow this gap to ensure that future advances within the field are derived from and benefit a more representative group of patients.

The road to rheumatoid arthritis prevention: challenges and opportunities.

Rheumatoid arthritis (RA) is the most prevalent cause of chronic arthritis worldwide and contributes substantial health burden and socioeconomic costs, issues that are magnified by the aging population. Despite significantly improved outcomes in the management of RA with earlier diagnosis and advances in treatment, there is still no cure and disease prevention remains an area of intense interest. Studies examining different treatment regimens in varied subsets of patients with pre-clinical RA have been able to delay but not prevent onset of frank RA. In this timely issue of Clinical Rheumatology, Alpziar-Rodriguez D. and Finckh A. highlight the available literature on pre-clinical RA including modifiable risk factors, results of key intervention trials, and discuss whether prevention of RA is on the horizon. We offer additional thoughts on current areas of uncertainty in RA prevention studies, lessons to be learned from prevention trials in other disease states, and future directions to consider.

CD52 Is Elevated on B cells of SLE Patients and Regulates B Cell Function.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell dysregulation and breaks in tolerance that lead to the production of pathogenic autoantibodies. We performed single-cell RNA sequencing of B cells from healthy donors and individuals with SLE which revealed upregulated CD52 expression in SLE patients. We further demonstrate that SLE patients exhibit significantly increased levels of B cell surface CD52 expression and plasma soluble CD52, and levels of soluble CD52 positively correlate with measures of lupus disease activity. Using CD52-deficient JeKo-1 cells, we show that cells lacking surface CD52 expression are hyperresponsive to B cell receptor (BCR) signaling, suggesting an inhibitory role for the surface-bound protein. In healthy donor B cells, antigen-specific BCR-activation initiated CD52 cleavage in a phospholipase C dependent manner, significantly reducing cell surface levels. Experiments with recombinant CD52-Fc showed that soluble CD52 inhibits BCR signaling in a manner partially-dependent on Siglec-10. Moreover, incubation of unstimulated B cells with CD52-Fc resulted in the reduction of surface immunoglobulin and CXCR5. Prolonged incubation of B cells with CD52 resulted in the expansion of IgD+IgMlo anergic B cells. In summary, our findings suggest that CD52 functions as a homeostatic protein on B cells, by inhibiting responses to BCR signaling. Further, our data demonstrate that CD52 is cleaved from the B cell surface upon antigen engagement, and can suppress B cell function in an autocrine and paracrine manner. We propose that increased expression of CD52 by B cells in SLE represents a homeostatic mechanism to suppress B cell hyperactivity.

Unraveling Race, Socioeconomic Factors, and Geographical Context in the Heterogeneity of Lupus Mortality in the United States.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease disproportionately affecting women and racial/ethnic minorities. We examined SLE-related mortality over time to assess whether the impact of race is attenuated when social economic status (SES) and geographic context are also considered. METHODS: This study examined whether social environment attenuates racial disparities in SLE-related mortality using race-geographical combinations of the US population known as the "Eight Americas." This framework jointly characterizes race, SES, and geographical location in relation to health disparities in the United States. Using National Vital Statistics and US Census data, we estimated mortality parameters for each of the Eight Americas. RESULTS: We identified 24 773 SLE deaths (2003-2014). Average annual mortality rates were highest among blacks in three race-geographical contexts: average-income blacks, southern low-income blacks, and high-risk urban blacks (14 to 15 deaths per million population) and lowest among nonblacks living in average-income settings (3 to 4 deaths per million population). Age at death was lowest (~47.5 years) for blacks and Asians and highest among low-income rural whites (~64.8 years). CONCLUSION: Blacks sharing the same social and geographical contexts as whites were disproportionately more likely to die young. Although blacks inhabited three vastly different contexts, SLE-related mortality parameters did not vary among socially advantaged and disadvantaged blacks. These findings suggest that race may transcend SES and geographical parameters as a key determinant of SLE-related mortality.

A promising approach to targeting type 1 IFN in systemic lupus erythematosus.

Despite advances in understanding systemic lupus erythematosus (SLE) pathogenesis, most clinical trials of new targeted therapies have been met with disappointment. The type I IFN pathway is believed to play an important role in SLE, and the proposed involvement of this pathway helps explain the frustration behind the failure at targeting either IFN-α or the type 1 IFN receptor itself. In this issue of the JCI, Furie et al. report on an intriguing phase 1b study that demonstrates an approach for inhibiting this pathway in the skin using an mAB (BIIB059) that targets the blood DC antigen 2 (BDCA-2) receptor on plasmacytoid DCs (pDCs). BIIB059 decreased IFN expression and improved cutaneous lupus disease activity, with a favorable safety profile. Whether or not this strategy will be effective in managing SLE in other organs remains unanswered. However, these results suggest that closing the door on targeting the type 1 IFN pathway in SLE may be premature and highlight the emerging question of whether an organ-specific approach toward lupus trials and treatment should be the wave of the future.

Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies.

OBJECTIVE: Women with systemic lupus erythematosus (SLE) are at a greater risk of preterm delivery, many of which may be medically indicated (iatrogenic). We investigated preterm delivery phenotypes in SLE and general population comparators and assessed the role of preeclampsia. STUDY DESIGN: We used population-based Swedish Register data (2001-2013) and defined maternal SLE as ≥2 SLE-coded discharge diagnoses from the Patient Register with ≥1 coded by an appropriate specialist. Women from the general population were identified using the Total Population Register. Preterm delivery was defined as <37 weeks and separated into spontaneous and iatrogenic, as well as later versus extremely preterm (32 to <37 weeks vs. <32 weeks). Maternal comorbidity was assessed, and the proportion mediated by preeclampsia was calculated examining first, subsequent, and all pregnancies. RESULTS: Preterm delivery was more common in SLE for the first (22 vs. 6%) and subsequent (15 vs. 4%) pregnancies among 781 SLE-exposed pregnancies and 11,271 non-SLE pregnancies. Of SLE-exposed first births, 27% delivered before 32 weeks, and 90% were iatrogenic (compared with 47% of non-SLE first births). CONCLUSION: Preterm delivery complicates a greater proportion of SLE pregnancies than general population pregnancies, and a considerable proportion of risk is mediated through preeclampsia.

Do Death Certificates Underestimate the Burden of Rare Diseases? The Example of Systemic Lupus Erythematosus Mortality, Sweden, 2001-2013.

OBJECTIVES: Mortality due to rare diseases, which are substantial sources of premature mortality, is underreported in mortality studies. The objective of this study was to determine the completeness of reporting systemic lupus erythematosus (SLE) as a cause of death. METHODS: In 2017, we linked data on a Swedish population-based cohort (the Swedish Lupus Linkage, 2001-2013) comprising people with SLE (n = 8560) and their matched general population comparators (n = 37 717) to data from the Cause of Death Register. We reviewed death records of deceased people from the cohort (n = 5110) and extracted data on patient demographic characteristics and causes of death. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for not reporting SLE as a cause of death by using multivariable-adjusted logistic regression models. RESULTS: Of 1802 deaths among SLE patients in the study, 1071 (59%) did not have SLE reported on their death records. Most SLE decedents were aged 75-84 at death (n = 584, 32%), female (n = 1462, 81%), and born in Nordic countries (n = 1730, 96%). Decedents aged ≥85 at death were more likely to have SLE not reported on their death records than were decedents aged <50 (OR = 2.34; 95% CI, 1.48-3.68). Having renal failure listed as a cause of death decreased the likelihood of SLE not being reported on the death record (OR = 0.54; 95% CI, 0.40-0.73), whereas having cancer listed as a cause of death increased this likelihood (OR = 2.39; 95% CI, 1.85-3.07). CONCLUSIONS: SLE was greatly underreported as a cause of mortality on death records of SLE patients, particularly in older decedents and those with cancer, thereby underestimating the true burden of this disease. Public health resources need to focus on improving the recording of rare diseases in order to enhance the epidemiological utility of mortality data.

The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus.

PURPOSE OF REVIEW: This review evaluated gender and race/ethnic representation in randomized controlled trials (RCTs) of patients with systemic lupus erythematosus (SLE). RECENT FINDINGS: Whites comprise 33% of prevalent SLE cases and comprised 51% of RCT enrollees. Blacks encompass 43% of prevalent SLE cases, but only represented 14% of RCT enrollees. Hispanics comprise 16% of prevalent SLE cases and 21% of RCT enrollees, while Asians comprise 13% of prevalent SLE cases and 10% of RCT enrollees. Males encompass 9% of SLE cases and 7% of RCT enrollees. The reporting and representation of males have remained stable over time, although their representation in RCTs is slighter lower than the prevalence of SLE in males. The representation of Hispanics, Asians, and Native Americans increased over time. However, the representation of blacks among RCT participants has decreased since 2006-2011. RCTs among SLE patients need larger sample sizes in order to evaluate heterogeneity in outcomes among racial subgroups. It is imperative that novel strategies be developed to recruit racial minorities with SLE by identifying and improving barriers to RCT enrollment in order to better understand the disease's diverse population.

Impact of Sex on Systemic Lupus Erythematosus-Related Causes of Premature Mortality in the United States.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is a source of significantly decreased life expectancy in the United States. This study investigated causes of deaths among males and females with SLE. MATERIALS AND METHODS: This cross-sectional study used the national death certificate database of ∼2.7 million death records in the United States, 2014. SLE was defined using Tenth Revision of the International Classification of Diseases codes: M32.1, M32.9, and M32.8. We compared sex-stratified demographic characteristics and the most commonly listed comorbidities in decedents with and without SLE. Relative risks (RRs) quantified the risk of dying with the most commonly listed comorbidities among decedents with SLE aged ≤50 years compared with non-SLE decedents. RESULTS: There were 2,036 decedents with SLE in the United States (86.2% female). Female SLE decedents were 22 years younger than non-SLE females (median: 59 years vs. 81 years). This difference was 12 years among male decedents (median: 61 years vs. 73 years). The most frequently listed causes of death among female SLE decedents were septicemia (4.32%) and hypertension (3.04%). In contrast, heart disease (3.70%) and diabetes mellitus with complications (3.61%) were the most common among male SLE decedents. Among younger male decedents, SLE had higher co-occurrence of coagulation/hemorrhagic disorders and chronic renal failure compared with non-SLE (RR = 16.69 [95% confidence interval {CI} = 10.50-27.44] and RR = 5.76 [95% CI = 2.76-12.00], respectively). These also contributed to premature mortality among women (RR = 4.98 [95% CI = 3.69-6.70] and 8.55 [95% CI = 6.89-10.61], respectively). CONCLUSIONS: Our findings identify clinically relevant comorbidities that may warrant careful consideration in patients' clinical management and the natural history of SLE.

Long-term management of gout: nonpharmacologic and pharmacologic therapies.

Gout is a common disorder with clinical signs and symptoms resulting from inflammatory responses to monosodium urate crystals deposited in tissues from extracellular fluids saturated for urate. Long-term management of gout focuses on nonpharmacologic and pharmacologic means to achieve and maintain serum urate levels in a subsaturating range. Despite a firm understanding of gout pathophysiology, means to achieve certain diagnosis, and a variety of effective therapies, treatment outcomes remain suboptimal. In this review, available nonpharmacologic and pharmacologic therapies for chronic gout are discussed and a framework is provided for successful achievement and maintenance of goal-range serum urate levels.