Associations between CD70 methylation of T cell DNA and age in adults with systemic lupus erythematosus and population controls: The Michigan Lupus Epidemiology & Surveillance (MILES) Program.

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 [ß = 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 (ß = 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.

Glucocorticoid-induced osteoporosis in premenopausal women: management for the rheumatologist.

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.

Cost-related prescription non-adherence and patient-reported outcomes in systemic lupus erythematosus: The Michigan Lupus Epidemiology & Surveillance program.

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: ß coeff 2.7 (95% CI 1.3, 4.1), p < 0.001] and damage [LDIQ ß 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.

Advances in the clinical use of hydroxychloroquine levels.

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.

Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature.

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.

The use of mycophenolate mofetil area under the curve.

PURPOSE OF REVIEW: Although mycophenolate mofetil (MMF) has been used successfully to treat a myriad of autoimmune diseases, its complex pharmacokinetics make it difficult to determine the true drug exposure for an individual patient. This review summarizes the body of literature focused on the gold standard measurement of the area under the curve (AUC) of mycophenolic acid (MPA), the active metabolite of MMF. RECENT FINDINGS: Fixed dosing of MMF leads to highly variable drug exposure. Retrospective series have reported improved clinical outcomes when a minimum AUC value from 0 to 12 h (AUC0-12h) ≥30 mg h/l is achieved. MPA levels are affected by various drug interactions, hypoalbuminemia, and renal insufficiency and the measurement of free rather than total MPA levels is prudent in some situations. A limited number of studies employing prospective dose adjustment of MMF based on AUC0-12h measurements have yielded mixed results. SUMMARY: Given the wide range of MPA AUC encountered in autoimmune diseases, dose adjustments of MMF based on AUC rather than fixed dosing of MMF should be considered in both clinical practice and clinical trials. Limited sampling strategies have been proposed to improve clinical feasibility of measurements, but a standard is yet to be defined.

Treatment of primary and secondary immune thrombocytopenia.

PURPOSE OF REVIEW: Medical therapies for the treatment of immune thrombocytopenia (ITP) complicating SLE are increasingly being investigated as alternatives to splenectomy and IVIG. The purpose of this review is to highlight the therapies that are utilized in the treatment of primary ITP and ITP secondary to lupus. RECENT FINDINGS: Corticosteroids are still the standard initial treatment of ITP, with the addition of IVIG when a rapid response is needed. There are few studies dedicated to assessing the efficacy of disease-modifying antirheumatic (DMARD), biologic, and nonimmunosuppressive agents as treatment for lupus thrombocytopenia/lupus ITP. Rituximab and thrombopoeitin mimetics have been the most extensively studied therapies for primary ITP in recent years. Results of trials show adequate initial responses; however, the duration of therapy and sustainability of responses are variable. Splenectomy is less often utilized. SUMMARY: Although corticosteroids, intravenous immunoglobulin and splenectomy have proven to be effective measures to treat immune thrombocytopenia, newer studies have demonstrated positive outcomes of immunosuppressives and thrombopoeitin mimetics. In most cases, the reported duration of therapy was not prolonged. More studies are needed to fully assess the effect of medical therapy in lupus ITP and to determine how long to continue maintenance therapy.

Cryptic conspirators: a conversation about thrombocytopenia and antiphospholipid syndrome.

PURPOSE OF REVIEW: Although antiphospholipid syndrome (APS) is best known for conveying increased risk of thrombotic events and pregnancy morbidity, thrombocytopenia is also recognized as a common association. In this review, we will explore the relationship between thrombocytopenia and APS, highlighting our evolving understanding - and persistent knowledge gaps - through clinically oriented questions and answers. RECENT FINDINGS: A history of thrombocytopenia likely portends a more severe APS phenotype (including increased risk of thrombosis). Although the pathophysiology underlying thrombocytopenia in APS has yet to be definitively revealed, mechanisms that play a role (at least in subsets of patients) include: immune thrombocytopenic purpura/ITP-like autoantibodies against platelet glycoproteins; antiphospholipid antibody (aPL)-mediated platelet activation and consumption; and potentially life threatening thrombotic microangiopathy. Although thrombocytopenia is often 'mild' in APS (and therefore, may not require specific therapy), there are causes of acute-onset thrombocytopenia that mandate emergent work-up and treatment. When APS-related thrombocytopenia does require therapy, the approach must be individualized (requiring an understanding of pathophysiology in the particular APS patient). For patients with ITP-like disease, rituximab is emerging as a popular approach to treatment; in contrast, there are hints that thrombopoietin mimetics may be associated with elevated thrombotic risk. SUMMARY: Thrombocytopenia is common in APS, and is likely associated with more severe disease. Improved understanding of thrombocytopenia in APS has the potential to improve risk stratification, reveal novel aspects of APS pathophysiology, and lead to treatments that are more individualized and holistic.

Multicriteria decision analysis process to develop new classification criteria for systemic lupus erythematosus.

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.

Prescription Opioid Use in Patients With and Without Systemic Lupus Erythematosus - Michigan Lupus Epidemiology and Surveillance Program, 2014-2015.

Rheumatic diseases are a leading cause of chronic, noncancer pain. Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease characterized by periodic flares that can result in irreversible target organ damage, including end-stage renal disease. Both intermittent and chronic musculoskeletal pain, as well as fibromyalgia (considered a centralized pain disorder due to dysregulation of pain processing in the central nervous system), are common in SLE. Opioids are generally not indicated for long-term management of musculoskeletal pain or centralized pain (fibromyalgia) because of lack of efficacy, safety issues ranging from adverse medical effects to overdose, and risk for addiction (1,2). In this study of 462 patients with SLE from the population-based Michigan Lupus Epidemiology and Surveillance (MILES) Cohort and 192 frequency-matched persons without SLE, nearly one third (31%) of SLE patients were using prescription opioids during the study period (2014-2015), compared with 8% of persons without SLE (p<0.001). Among the SLE patients using opioids, 97 (68%) were using them for >1 year, and 31 (22%) were concomitantly on two or more opioid medications. Among SLE patients, those using the emergency department (ED) were approximately twice as likely to use prescription opioids (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.6; p = 0.004). In SLE, the combined contributions of underlying disease and adverse effects of immunosuppressive and glucocorticoid therapies already put patients at higher risk for some known adverse effects attributed to long-term opioid use. Addressing the widespread and long-term use of opioid therapy in SLE will require strategies aimed at preventing opioid initiation, tapering and discontinuation of opioids among patients who are not achieving treatment goals of reduced pain and increased function, and consideration of nonopioid pain management strategies.

CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients.

OBJECTIVE: The goal of this study was to comprehensively characterize CD4+CD28+ T cells overexpressing CD11a and KIR genes, and examine the relationship between this T cell subset, genetic risk, and disease activity in lupus. METHODS: The size of the CD4+CD28+KIR+CD11ahi T cell subset was determined by flow cytometry, and total genetic risk for lupus was calculated in 105 female patients using 43 confirmed genetic susceptibility loci. Primary CD4+CD28+KIR+CD11ahi T cells were isolated from lupus patients or were induced from healthy individuals using 5-azacytidine. Genome-wide DNA methylation was analyzed using an array-based approach, and the transcriptome was assessed by RNA sequencing. Transcripts in the CDR3 region were used to assess the TCR repertoire. Chromatin accessibility was determined using ATAC-seq. RESULTS: A total of 31,019 differentially methylated sites were identified in induced KIR+CD11ahi T cells with >99% being hypomethylated. RNA sequencing revealed a clear pro-inflammatory transcriptional profile. TCR repertoire analysis suggests less clonotype diversity in KIR+CD11ahi compared to autologous KIR-CD11alow T cells. Similarly, primary KIR+CD11ahi T cells isolated from lupus patients were hypomethylated and characterized by a pro-inflammatory chromatin structure. We show that the genetic risk for lupus was significantly higher in African-American compared to European-American lupus patients. The demethylated CD4+CD28+KIR+CD11ahi T cell subset size was a better predictor of disease activity in young (age ≤ 40) European-American patients independent of genetic risk. CONCLUSION: CD4+CD28+KIR+CD11ahi T cells are demethylated and characterized by pro-inflammatory epigenetic and transcriptional profiles in lupus. Eliminating these cells or blocking their pro-inflammatory characteristics might present a novel therapeutic approach for lupus.

Diagnostic and therapeutic considerations in patients with hypogammaglobulinemia after rituximab therapy.

PURPOSE OF REVIEW: There are no established guidelines for evaluating and treating hypogammaglobulinemia in patients with rheumatic disease who receive B-cell depleting agents. The purpose of this article is to review findings in the work-up and treatment of common variable immunodeficiency (CVID) that can guide our evaluation of patients with autoimmune disease who develop hypogammaglobulinemia after rituximab/B-cell depleting therapy. RECENT FINDINGS: Infection rates are higher in rheumatic disease patients who develop hypogammaglobulinemia than those who do not. However, not all patients who develop hypogammaglobulinemia are at increased risk of developing infection after B-cell depleting therapy. Recent consensus statements have helped refine the diagnosis of impaired immune responses in patients with CVID, and can provide guidance for the diagnostic work-up and therapeutic decision making for patients with secondary drug induced hypogammaglobulinemia. SUMMARY: Based on findings in studies of CVID, assessment of vaccine response in patients with hypogammglogulinemia after rituximab therapy in the setting of recurrent infections can help predict propensity for infection and thus guide decision making with regards to intravenous immunoglobulin supplementation and retreatment with rituximab.

Update on maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis.

PURPOSE OF REVIEW: The antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitides are a group of rare systemic diseases. The past several years have seen major therapeutic advances in the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The success rate in induction of remission is high, but reducing the high incidence of relapses remains a therapeutic challenge. RECENT FINDINGS: Studies have shown no improvement in relapse rates in GPA and MPA over the past 2 decades. This has prompted a recent focus on therapeutic strategies to maintain remission in these relapsing diseases. Low-dose rituximab (RTX) at fixed intervals has been shown superior to azathioprine for maintenance of remission. Despite this advance, longer follow-up periods have shown late-stage relapses with withdrawal of therapy suggesting a possible need for longer treatment regimens. Evaluation of prognostic indicators is also helpful in stratifying patients who might be more likely to relapse or to respond to a particular therapy. SUMMARY: Results from recent research have significantly advanced our approach to prevention of relapses in GPA and MPA. Newer maintenance agents have shown benefit in maintenance of remission and relapse-free survival.

Endothelial progenitor dysfunction associates with a type I interferon signature in primary antiphospholipid syndrome.

OBJECTIVES: Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. METHODS: We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes. RESULTS: Endothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody. CONCLUSIONS: We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.

Treatment of catastrophic antiphospholipid syndrome.

PURPOSE OF REVIEW: Catastrophic antiphospholipid syndrome (CAPS) is a severe manifestation of antiphospholipid syndrome (APS). Although affecting only 1% of patients with APS, the condition is frequently fatal if not recognized and treated early. Here, we will review the current approach to diagnosis and treatment of CAPS. RECENT FINDINGS: Data from the international 'CAPS registry', spearheaded by the European Forum on Antiphospholipid Antibodies, have improved our understanding of at-risk patients, typical clinical features, and precipitating diagnoses. Current guidelines also continue to support the role of anticoagulants and glucocorticoids as foundation therapy in all patients. Finally, new basic science and case series suggest that novel therapies, such as rituximab and eculizumab, warrant further study. SUMMARY: Attention to associated diagnoses, such as infection and systemic lupus erythematosus (SLE), is critical at the time of diagnosis. All patients should be treated with anticoagulants, corticosteroids, and possibly plasma exchange. In patients with SLE, cyclophosphamide should be considered. In refractory or relapsing cases, new therapies, such as rituximab and possibly eculizumab, may be options, but need further study.

Suppression of normal immune responses after treatment with rituximab.

PURPOSE OF REVIEW: Because rituximab is increasingly used in systemic autoimmune diseases, alone or in combination with other immunosuppressive medication, secondary reduction of normal immune defenses has become a more significant clinical problem. RECENT FINDINGS: The goal of rituximab treatment of immune-mediated conditions is complete depletion of circulating B cells. Studies have suggested that lack of complete B-cell depletion is associated with nonresponse, and B-cell repletion can predict relapse. The resulting prolonged B-cell depletion is associated with risk of adverse effects including hypogammaglobulinemia, increased risk of infection, failure to develop immune responses after vaccination, and neutropenia. Pre-existing hypogammaglobulinemia has been linked to increased risk of reduction of IgG levels and serious infections after rituximab therapy, and concomitant cyclophosphamide therapy has been associated with an increased risk of developing hypogammaglobulinemia. SUMMARY: Although rituximab therapy is effective in the treatment of many systemic autoimmune diseases and has an acceptable safety profile, treating physicians need to keep in mind that pre-existing hypogammaglobulinemia and likely also use of additional immunosuppressive agents can increase the risk of prolonged hypogammaglobulinemia and infection. In keeping with current recommendations for rheumatoid arthritis, we recommend that all patients who undergo rituximab therapy have baseline IgG, IgM, and IgA measurements and also have immunoglobulin levels monitored periodically during treatment.

Renal involvement in lupus is characterized by unique DNA methylation changes in naïve CD4+ T cells.

Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement. The tyrosine kinase gene TNK2 involved in cell trafficking and tissue invasion, and the phosphatase gene DUSP5 which dephosphorylates and inhibits the ERK signaling pathway, were among the most hypomethylated. Independent of disease activity, renal involvement is characterized by more robust demethylation in interferon regulated genes differentially methylated in both sets of lupus patients with and without renal involvement (fold change 1.4, P = 0.0014). The type-I interferon master regulator gene IRF7 is only hypomethylated in lupus patients with renal involvement. IRF-7 is an upstream transcription factor that regulates several loci demethylated only with renal involvement such as CD80, HERC5, IFI44, IRF7, ISG15, ISG20, ITGAX, and PARP12 (P = 1.78 × 10(-6)). Among the CG sites only hypomethylated with renal involvement, CG10152449 in CHST12 has a sensitivity of 85.7% and a specificity of 64.3% for stratifying lupus patients for a history of renal involvement (P = 0.0029). Our data identified novel epigenetic susceptibility loci that are differentially methylated with renal involvement in lupus. These loci will help better understand lupus nephritis, and provide a proof of principle for the potential applicability of specific methylation changes as predictors for specific organ involvement in lupus.

Incidence and prevalence of systemic lupus erythematosus among Arab and Chaldean Americans in southeastern Michigan: the Michigan Lupus Epidemiology and Surveillance Program.

OBJECTIVES: We assessed the burden of systemic lupus erythematosus (SLE) among Arab and Chaldean Americans residing in southeast Michigan. METHODS: For those meeting SLE criteria from the Michigan Lupus Epidemiology and Surveillance Registry, we determined Arab or Chaldean ethnicity by links with demographic data from birth certificates and with a database of Arab and Chaldean names. We compared prevalence and incidence of SLE for Arab and Chaldean Americans with estimates for non-Arab and non-Chaldean American Whites and Blacks. RESULTS: We classified 54 individuals with SLE as Arab and Chaldean Americans. The age-adjusted incidence and prevalence estimates for Arab and Chaldean Americans were 7.6 and 62.6 per 100 000, respectively. Arab and Chaldean Americans had a 2.1-fold excess SLE incidence compared with non-Arab and non-Chaldean American Whites. Arab and Chaldean American women had both significantly higher incidence rates (5.0-fold increase) and prevalence estimates (7.4-fold increase) than did Arab and Chaldean American men. CONCLUSIONS: Recognizing that Arab and Chaldean Americans experience different disease burdens from Whites is a first step toward earlier diagnosis and designing targeted interventions. Better methods of assigning ethnicity would improve research in this population.

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial.

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.