This target product profile (TPP) highlights the minimal and optimal characteristics for ex-vivo and in-vivo cell and gene therapy-based products aimed at achieving an HIV cure (ie, durable antiretroviral-free viral control). The need for an effective, safe, scalable, affordable, accessible, and acceptable cure for HIV infection remains a major global priority. The possibilities for cell and gene therapy-based products for an HIV cure are rapidly expanding. In a multi-stakeholder consensus process of clinical experts and civil society, including representatives from low-income and middle-income countries, participants generally agreed on the optimal targets, whereas consensus on the minimal targets was not reached on every parameter. There was less agreement on the minimal targets for ex-vivo than in-vivo therapies given the complexity of ex-vivo interventions. The TPP is planned to be updated at regular intervals. Building a TPP, such as this one, is an important process for stakeholder engagement and aligning ambitions for the development of products that are acceptable to both clinicians and civil society.

Sixty years ago, Fessas and Stamatoyannopoulos noticed that patients with hereditary persistence of fetal hemoglobin have a milder course of beta -thalassemia than other patients with the condition.(1) Later, Nienhuis and Stamatoyannopoulos postulated that stimulation of the production of fetal hemoglobin might provide a therapeutic benefit to adults with sickle cell disease or severe variants of homozygous beta -thalassemia, and Platt et al. showed that higher levels of fetal hemoglobin were associated with prolonged survival.(2,3) In articles and a letter now published in the Journal, Frangoul et al.(4) and Locatelli et al.(5) describe the successful treatment of sickle cell disease and transfusion-dependent . . .

BACKGROUND:Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. METHODS:This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. FINDINGS:Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). INTERPRETATIONS:Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. FUNDING:The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

As we commemorate the 20th anniversary of the U.S. President's Emergency for AIDS Relief (PEPFAR), there is much to celebrate: over 20 million persons with HIV are receiving life-saving antiretroviral treatment (ART) in over 50 PEPFAR-supported countries [1]. However, external financial support for HIV in low- and middle-income countries (LMICs) remains flat, and overall resources are estimated to be at least $8 billion short of the $29 billion needed to reach the 2025 goals of 95-95-951 [2]. Even if these goals are realized, they will only be sustained if resources are provided indefinitely. The prospect of HIV “cure,” that is durable ART-free suppression of HIV, represents an attractive alternative to such ongoing resource commitments—beckoning investment in an intervention that would extend lives, reduce new HIV acquisitions and obviate the need for continued ART. With this in mind, we read with interest the report in this journal by Guzauskas and Hallet [3] on “the long-term impact and value of curative therapy for HIV.” Modelling the health benefits of such an intervention, they found that “HIV cure” would more rapidly lower HIV prevalence, prevent future acquisitions over time, increase life years in the population and reduce AIDS-related deaths when compared to ART alone even in LMICs. These benefits were even more pronounced in settings with higher HIV burdens and lower ART adherence. They also found that such an intervention would be cost-effective for the duration of HIV patients’ lifetimes if price aligned with a country's per capita income and disease burden. As has been pointed out [4, 5], even though the timeline to successive generations of curative interventions remains indeterminate, there are important considerations to be addressed sooner rather than later. For instance, the development of a target product profile that envisions application to populations in diverse settings, including LMICs, is an important step requiring updates informed by scientific advances [5]. Though efforts to engage key stakeholders and build capacity enabling widespread access to these interventions in LMICs are already underway, they must in the future expand as candidate cures move to the clinic [5, 6]. Of note, many of the activities now supported by PEPFAR for ART scale-up and treatment monitoring are perfectly suited to the introduction of an HIV cure intervention. We applaud the work of Guzauskas and Hallet for advocating for early anticipation of resource needs for cure interventions to ensure widespread access in LMICs. For the investment to be cost-effective and adopted across countries with diverse income levels and HIV disease burdens, tailored pricing might be offered that accounts for the current costs of delivering lifelong ART, the value of improved health among those living with HIV and projected savings from averted HIV acquisitions. New approaches to financing the implementation of an HIV cure will be needed so that implementation can be global, equitable and appropriately paced. PEPFAR, along with other donors and stakeholders, would seem to be well poised to further catalyse this and other efforts, working with country governments, regulatory agencies and the community to realize the promise of a cure for HIV, thereby accelerating the elimination of this deadly virus around the world. The authors have no competing interests to declare. ER: Original draft of the manuscript and subsequent edits. JB: Contributed to the economic issues raised. JMMc: Contributed to the overall message of the manuscript and the specific technical components of HIV cure. MD: Contributed to the overall message of the manuscript and the specific technical components of HIV cure with a focus on LMICs. The authors wish to acknowledge the HIV Cure in Africa Acceleration Program (HCAAP), all scientists engaged in HIV cure research, their study participants, and the growing number of community groups supporting HIV cure in LMICs. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the United States Centers for Disease Control and Prevention. Data derived from public domain resources.

Erratum to: Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner? doi: 10.20411/pai.v8i2.665 In the original publication, the comments provided by Santiago Ávila-Ríos were mistakenly omitted. In this version, his comments are included in the “Comments by Leaders” section, and his name has been included in the list of authors. --- Once a death sentence, HIV is now considered a manageable chronic disease due to the development of antiretroviral therapy (ART) regimens with minimal toxicity and a high barrier for genetic resistance. While highly effective in arresting AIDS progression and rendering the virus untransmissible in people living with HIV (PLWH) with undetectable viremia (U=U) [1, 2]), ART alone is incapable of eradicating the “reservoir” of resting, latently infected CD4+ T cells from which virus recrudesces upon treatment cessation. As of 2022 estimates, there are 39 million PLWH, of whom 86% are aware of their status and 76% are receiving ART [3]. As of 2017, ART-treated PLWH exhibit near normalized life expectancies without adjustment for socioeconomic differences [4]. Furthermore, there is a global deceleration in the rate of new infections [3] driven by expanded access to pre-exposure prophylaxis (PrEP), HIV testing in vulnerable populations, and by ART treatment [5]. Therefore, despite outstanding issues pertaining to cost and access in developing countries, there is strong enthusiasm that aggressive testing, treatment, and effective viral suppression may be able to halt the ongoing HIV epidemic (ie, UNAIDS’ 95-95-95 targets) [6–8]; especially as evidenced by recent encouraging observations in Sydney [9]. Despite these promising efforts to limit further viral transmission, for PLWH, a “cure” remains elusive; whether it be to completely eradicate the viral reservoir (ie, cure) or to induce long-term viral remission in the absence of ART (ie, control; Figure 1). In a previous salon hosted by Pathogens and Immunity in 2016 [10], some researchers were optimistic that a cure was a feasible, scalable goal, albeit with no clear consensus on the best route. So, how are these cure strategies panning out? In this commentary, 8 years later, we will provide a brief overview on recent advances and failures towards identifying determinants of viral persistence and developing a scalable cure for HIV. Based on these observations, and as in the earlier salon, we have asked several prominent HIV cure researchers for their perspectives.

Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.

IntroductionDespite progress in systemic lupus erythematosus (SLE) treatment, challenges persist in medication adherence due to side effects and costs. Precision nutrition, particularly adjusting fatty acid intake, offers a cost-effective strategy for enhancing SLE management. Prior research, including our own, indicates that increased consumption of omega-3 polyunsaturated fatty acids (PUFAs) correlates with improved outcomes in SLE patients. Here we build upon these findings by investigating associations between serum fatty acids—grouped as PUFAs, monounsaturated fatty acids (MUFAs), and saturated fatty acids (SFAs)—and lupus activity, pain, and sleep disturbance.MethodsUsing data from 418 participants with SLE in the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort, we examined associations between serum levels of 25 fatty acids determined by GC-MS and patient-reported outcomes. Disease activity, pain, and sleep quality were assessed using standardized questionnaires. Generalized additive models and partial residual plots were utilized to examine the linearity of fatty acid effects. Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO), followed by multiple linear regression adjusting for sociodemographic factors.ResultsFindings indicated favorable associations between ω-3 PUFAs—and, to a lesser extent, ω-6 PUFAs—and patient-reported outcomes, while MUFAs and SFAs showed unfavorable associations. Docosahexaenoic acid (DHA), an omega-3 PUFA, exhibited the most robust favorable associations across all outcomes. Additionally, the omega-3 α-linolenic acid (ALA) was linked to reduced pain, whereas eicosapentaenoic acid (EPA), another omega-3, was associated with worsened disease activity and pain. Among omega-6 PUFAs, dihomo-γ-linolenic acid (DGLA) was favorably associated with disease activity, while the omega-9 PUFA Mead acid was linked to increased pain.DiscussionThese findings underscore the prospect that increased tissue levels of long-chain omega-3 PUFAs, particularly DHA, are favorably associated with SLE outcomes. Although further research is needed to establish causal relationships, existing evidence supports the role of omega-3 PUFAs in managing cardiovascular and chronic kidney disease, common SLE comorbidities. Most study participants exhibited low omega-3 PUFA status, suggesting substantial potential for improvement through targeted dietary interventions and supplementation. This study supports a potential role for precision nutrition in comprehensive SLE management, considering the impact of PUFAs, SFAs and MUFAs.

PURPOSE OF REVIEW:Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medications initially developed for the treatment of diabetes, although their cardiac and renal protective benefits are far reaching. There has been marked interest in the rheumatology community to adopt these medications into our clinical practice, particularly for chronic kidney disease with persistent proteinuria. RECENT FINDINGS:SGLT2 inhibitors have been approved for patients with type 2 diabetes mellitus, heart failure with reduced or preserved ejection fraction, atherosclerotic cardiovascular disease in the setting of type 2 diabetes mellitus, as well as chronic kidney disease with proteinuria. Large studies on SGLT2 inhibitors have largely excluded patients with proteinuric chronic kidney disease due to autoimmune glomerulonephritis due to concerns for confounding from immunosuppression. The Dapagliflozin and Prevention of Adverse Outcomes in CKD Trial (DAPA-CKD) showed that SGLT2 inhibition decreased progression of renal disease in patients with IgA nephropathy. Expanding this to other autoimmune glomerulonephropathies, several small studies have shown improvements in proteinuria in patients with lupus nephritis treated with SGLT2 inhibitors. A study evaluating safety of SGLT2 inhibitors in patients with lupus identified no specific concerns even with concomitant use of immunosuppression. SUMMARY:Small studies have shown that SGLT2 inhibitors can been utilized safely and efficaciously in patients with lupus nephritis. Additional research is needed to identify where these medications fit into the rheumatology treatment armamentarium.

Therapeutic innovation to address sickle cell disease (SCD) is at a historical apex, characterized by a drug discovery, development, and commercialization landscape that includes potentially curative gene therapies. Given the wide geographic distribution of SCD, with a major presence in Africa, it is imperative that new medicines are designed to meet the speci fi c needs of persons with SCD everywhere. Target product pro fi les (TPPs) detail the desired attributes of new medicines and serve as a guide for drug developers. To support research efforts for curative treatments for SCD, we mobilized a large multi-disciplinary expert group to generate consensus-driven TPPs for ex vivo and in vivo SCD gene therapies, utilizing a modi fi ed Delphi methodology supplemented with virtual workshops. The main fi ndings are TPPs that describe 20 minimal and optimal criteria for novel gene therapy products in categories of scope (3 criteria), performance/safety (11 criteria), manufacturing (4 criteria), and administration (2 criteria). TPPs for ex vivo and in vivo products differed in some performance/safety criteria and all criteria pertaining to manufacturing and administration. These outputs will ideally support development of durable treatments that are safe, ef fi cacious, and practical for persons with SCD in global settings.

Objective Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity. Methods The recombinant PR3 variants, iPR3 which is clinically used to detect PR3-ANCAs and iHm5 which contains three point mutations in Epitope 1 and 5 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) clinical trials were used to screen the differential PR3-ANCA binding. Selective binding was determined by inhibition experiments. Results Rather than a reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with iPR3. A monoclonal ANCA (moANCA518) from a patient with GPA was found to selectively bind to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 contained in Epitope 1 and 5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518. Conclusion The preferential binding of PR3-ANCAs from patients like the selective binding of moANCA518 to iHm5 is conferred by increased antigenicity of Epitope 3 on iHm5. This can also be induced on iPR3 when it is captured by monoclonal antibody MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches.

The switch from primitive to definitive hematopoiesis occurs early in development through the emergence of a wave of definitive hematopoietic stem cells from intraembryonic sites, supplanting the original primitive population of extraembryonically derived stem cells. When it became clear that unique features of the fetal immune system could not be reproduced by adult stem cells, it was hypothesized that a lineage of definitive fetal hematopoietic stem cells predominates antenatally, ultimately giving way to an emerging wave of adult stem cells and resulting in a "layered" fetal immune system consisting of overlapping lineages. It is now clear, however, that the transition from human fetal-to-adult T cell identity and function does not occur due to a binary switch between distinct fetal and adult lineages. Rather, recent evidence from single cell analysis suggests that during the latter half of fetal development a gradual, progressive transition occurs at the level of hematopoietic stem-progenitor cells (HSPCs) which is reflected in their T cell progeny. At a transcriptional level, clusters of genes are up- and down-regulated with sequenced timing, suggesting that the transition is under the control of master regulatory factors, including epigenetic modifiers. The net effect is still one of "molecular layering," that is, the continuous layering of iterative generations of HSPCs and T cells that arise through progressive changes in gene expression. This review will focus on recent discoveries that elucidate mechanisms of fetal T cell function and the transition from fetal to adult identity. The epigenetic landscape of fetal T cells facilitates their ability to fulfill the dominant fetal mandate of generating tolerance against self, maternal, and environmental antigens by supporting their predisposition to differentiate into CD25+ FoxP3+ regulatory T cells (TRegs ). We will explore how the coordinated development of two complementary populations of fetal T cells-conventional T cells dominated by TRegs and tissue-associated memory effector cells with innate-like inflammatory potential-is crucial not only for maintaining intrauterine immune quiescence but also for facilitating an immune response that is appropriately tuned for the bombardment of antigen stimulation that happens at birth.

Thoroughly revised and updated to include contemporary terms that have gained importance such as furlough, unconscious bias, platform work, and Great Resignation, this second edition of the Encyclopedia of Human Resource Management is an authoritative and comprehensive reference resource comprising almost 400 entries on core HR areas and concepts.

Purpose of review This review seeks to summarize the literature relevant to the treatment of glucocorticoid-induced osteoporosis in premenopausal women; an issue commonly encountered by rheumatologists and yet lacking good clinical practice guidelines. Recent findings Although most of the relevant literature on osteoporosis includes postmenopausal women only, data from both randomized controlled trials and case reports suggest bisphosphonates can be an effective and well tolerated treatment for premenopausal patients. Data for other medications to treat premenopausal osteoporosis is less robust. Summary The use of bisphosphonates in young women may be safer than initially thought and should likely be used for the treatment of glucocorticoid-induced osteoporosis in rheumatology clinics. Further research is needed to continue to understand long-term risk.

Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. Here, in the same 37 male PWH on ART we measure longitudinal kinetics of HIV DNA and cell turnover rates in five CD4 cell subsets: naïve (T N ), stem-cell- (T SCM ), central- (T CM ), transitional- (T TM ), and effector-memory (T EM ). HIV decreases in T TM and T EM but not in less-differentiated subsets. Cell turnover is ~10 times faster than HIV clearance in memory subsets, implying that cellular proliferation consistently creates HIV DNA. The optimal mathematical model for these integrated data sets posits HIV DNA also passages between CD4 cell subsets via cellular differentiation. Estimates are heterogeneous, but in an average participant’s year ~10 (in T N and T SCM ) and ~10 4 (in T CM , T TM , T EM ) proviruses are generated by proliferation while ~10 3 proviruses passage via cell differentiation (per million CD4). In simulations, therapies blocking proliferation and/or enhancing differentiation could reduce HIV DNA by 1-2 logs over 3 years. In summary, HIV exploits cellular proliferation and differentiation to persist during ART but clears faster in more proliferative/differentiated CD4 cell subsets and the same physiological mechanisms sustaining HIV might be temporarily modified to reduce it.

Objectives Medication access and adherence play key roles in determining patient outcomes. We investigated whether cost-related non-adherence (CRNA) to prescription medications was associated with worse patient-reported outcomes in a population-based systemic lupus erythematosus (SLE) cohort. Methods Sociodemographic and prescription data were collected by structured interviews in 2014–2015 from patients meeting SLE criteria in the established Michigan Lupus Epidemiology & Surveillance (MILES) Cohort. We examined the associations between CRNA and potential confounders such as sociodemographics and health insurance coverage, and outcome measures of SLE activity and damage using multivariable linear regression. Results 462 SLE participants completed the study visit: 430 (93.1%) female, 208 (45%) Black, and mean age 53.3 years. 100 (21.6%) participants with SLE reported CRNA in the preceding 12 months. After adjusting for covariates, CRNA was associated with both higher levels of current SLE disease activity [SLAQ: β coeff 2.7 (95% CI 1.3, 4.1), p < 0.001] and damage [LDIQ β coeff 1.4 (95% CI 0.5, 2.4), p = 0.003]. Race, health insurance status, and fulfilling Fibromyalgia (FM) Survey Criteria were independently associated with both higher (worse) SLAQ and LDIQ scores; female sex was further associated with higher SLAQ scores. Conclusion Patients with SLE who reported CRNA in the previous 12 months had significantly worse self-reported current disease activity and damage scores compared to those not reporting CRNA. Raising awareness and addressing barriers or concerns related to financial implications and accessibility issues in care plans may help to improve these outcomes.

Background: Environmental factors can influence epigenetic regulation, including DNA methylation, potentially contributing to systemic lupus erythematosus (SLE) development and progression. We compared methylation of the B cell costimulatory CD70 gene, in persons with lupus and controls, and characterized associations with age.Results: In 297 adults with SLE and 92 controls from the Michigan Lupus Epidemiology and Surveillance (MILES) Cohort, average CD70 methylation of CD4+ T cell DNA across 10 CpG sites based on pyrosequencing of the promoter region was higher for persons with SLE compared to controls, accounting for covariates [beta = 2.3, p = 0.011]. Using Infinium MethylationEPIC array data at 18 CD70-annoted loci (CD4+ and CD8+ T cell DNA), sites within the promoter region tended to be hypomethylated in SLE, while those within the gene region were hypermethylated. In SLE but not controls, age was significantly associated with pyrosequencing-based CD70 methylation: for every year increase in age, methylation increased by 0.14 percentage points in SLE, accounting for covariates. Also within SLE, CD70 methylation approached a significantly higher level in Black persons compared to White persons (beta = 1.8, p = 0.051). Conclusions: We describe altered CD70 methylation patterns in T lymphocyte subsets in adults with SLE relative to controls, and report associations particular to SLE between methylation of this immune-relevant gene and both age and race, possibly a consequence of "weathering" or accelerated aging which may have implications for SLE pathogenesis and potential intervention strategies.

The development of prophylatic or therapeutic medicines for infectious diseases is one of the priorities for health organizations worldwide. Innovative solutions are required to achieve effective, safe, and accessible treatments for most if not all infectious diseases, particularly those that are chronic in nature or that emerge unexpectedly over time. Genetic technologies offer versatile possibilities to design therapies against pathogens. Recent developments such as mRNA vaccines, CRISPR gene editing, and immunotherapies provide unprecedented hope to achieve significant results in the field of infectious diseases. This review will focus on advances in this domain, showcasing the cross-fertilization with other fields (e.g., oncology), and addressing some of the logistical and economic concerns important to consider when making these advances accessible to diverse populations around the world.

Objectives Lupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional lupus-associated DNA methylation changes and determine the genetic contribution to epigenetic changes characteristic of lupus. Methods Genome-wide DNA methylation was assessed in naïve CD4+ T cells from 74 patients with lupus and 74 age-matched, sex-matched and race-matched healthy controls. We applied a trend deviation analysis approach, comparing methylation data in our cohort with over 16 500 samples. Methylation quantitative trait loci (meQTL) analysis was performed by integrating methylation profiles with genome-wide genotyping data. Results In addition to the previously reported epigenetic signature in interferon-regulated genes, we observed hypomethylation in the promoter region of the miR-17-92 cluster in patients with lupus. Members of this microRNA cluster play an important role in regulating T cell proliferation and differentiation. Expression of two microRNAs in this cluster, miR-19b1 and miR-18a, showed a significant positive correlation with lupus disease activity. Among miR-18a target genes, TNFAIP3, which encodes a negative regulator of nuclear factor kappa B, was downregulated in lupus CD4+ T cells. MeQTL identified in lupus patients showed overlap with genetic risk loci for lupus, including CFB and IRF7. The lupus risk allele in IRF7 (rs1131665) was associated with significant IRF7 hypomethylation. However, <1% of differentially methylated CpG sites in patients with lupus were associated with an meQTL, suggesting minimal genetic contribution to lupus-associated epigenotypes. Conclusion The lupus defining epigenetic signature, characterised by robust hypomethylation of interferon-regulated genes, does not appear to be determined by genetic factors. Hypomethylation of the miR-17-92 cluster that plays an important role in T cell activation is a novel epigenetic locus for lupus.

Systemic lupus erythematosus (SLE) is the prototypical multi-system autoimmune disease with diverse clinical features in persons with disease. SLE is also unified by characteristic autoimmunity directed against nucleic acid or nucleoprotein complexes. SLE is both more prevalent and typically exhibits a more severe clinical course in persons with African-American ancestry than in persons with European ancestry. The reasons for this discrepancy remain incompletely understood. GWAS studies of SLE in cohorts of individuals with Amerindian, East Asian and European ancestry have identified > 180 risk loci for SLE across the genome. These loci act in several pathways: clearance of autoantigens, innate immune response to nucleic acids, and lymphocyte activation. Despite these advances in understanding the genetic basis of SLE, a genome-wide association scan (GWAS) of SLE in a cohort of individuals with African-American ancestry has not yet been reported. Here, we report preliminary results of GWAS in 1494 SLE cases and 6076 matched controls with African-American ancestry. Illumina Infinium Omni 1, Omni 1S, Omni 2.5 and OmniExpress platforms were used for genotyping. Genotypes were imputed using the TOPMed reference panel at NHLBI. By defining the contribution common genetic variants to disease risk across the genome, our study represents a step towards understanding the genetic basis of SLE and the increased prevalence and severity of SLE in African ancestry populations. To fully define the relative contribution of environment and genetics to the discrepant SLE severity and prevalence observed in African-American populations, future studies will be necessary. These studies should focus both on comprehensive understanding of the environmental influences and comprehensive assessment of genome- wide genetic variation (i.e. whole-genome sequencing) that impact SLE risk and disease severity. Our results confirm genome-wide significant (P < 5E-8) association with loci ascertained in other populations (STAT4-STAT1, TNIP1, MIR146A, HLA-C4A-C4B, IRF5, BLK, PLAT-IKBKB, RELA-RNASEH2C-OVOL1, ITGAM, and IRF8) and identify several novel genome-wide significant risk loci that are newly described in our study (ENSA, IKBKB/Chr8: Centromere and PCMTD1-ST18). Further, we compared associated variants in our study with those from three large SLE GWAS studies in cohorts of individuals with European, East Asian and Amerindian ancestry. This comparison of SLE risk loci revealed pervasive sharing of SLE genetic risk across ancestral groups. For 70% of the risk loci, the lead marker exhibited nominal association (P < 0.05) with SLE in our GWAS of SLE in African- American persons. Importantly, the association of all such variants cohered with the reported direction in other ancestries. Overall, our findings are consistent with a polygenic contribution to SLE in African-American individuals that is largely shared across populations. We also find association with a rare variant (MAF < 1%) of large effect (OR = 3.91) near a locus previously identified via ImmunoChip (Illumina), PLAT-IKBKB. The lead variant at this locus is non-polymorphic in populations with ancestry outside of Africa. This association explains the increased risk of SLE in ~4% of cases in our cohort. On the one hand, our GWAS of SLE in persons African-American ancestry provides insights that reinforce the conclusions concerning the known risk loci from other ancestries. On the other hand, this mechanism uniquely raises SLE risk in a small proportion of African ancestry individuals with SLE. Together our findings reveal both uniformity and diversity of genetic risk factors impacting SLE development across populations.

PURPOSE OF REVIEW:This review summarizes the recent literature exploring hydroxychloroquine levels and their relationship with disease activity and risk of toxicity.RECENT FINDINGS:There is no clear correlation between weight-based dosing of hydroxychloroquine and the resulting blood levels of the medication. Recent studies have shown that increased hydroxychloroquine levels are associated with lower lupus disease activity and likely also increased risk of medication toxicity.SUMMARY:Mounting evidence supports use of hydroxychloroquine levels in clinical practice to document adherence and ensure safety.