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Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients.

ABSTRACT: Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or ELISA assays, the systemic phenotype of SLE patients not taking (MMF-) or taking (MMF+) MMF were studied. MMF+ SLE patients had significant reductions in total numbers of transitional B cells, plasmablasts, and T cells, specifically CD4+ Th17-type and CD4+ Treg-type cells, compared with MMF- patients. Plasma soluble mediators were decreased in MMF+ patients including chemokines (MIG/CXCL9 and SDF-1α/CXCL12) and growth factors (VEGF-A and PDGF-BB). Soluble mediators and cell subsets grouped by functional properties revealed significant modifications associated with STAT3 and B cell pathways. Further, healthy PBMCs treated with IL-6 revealed a reduction in p-STAT3 following the addition of mycophenolic acid (the active metabolite of MMF). In conclusion, the inhibition of STAT3 phosphorylation by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of p-STAT3 are associated with disease pathology.

SUBMITTER: Slight-Webb S

PROVIDER: S-EPMC6413783 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients.

Slight-Webb Samantha S Guthridge Joel M JM Chakravarty Eliza F EF Chen Hua H Lu Rufei R Macwana Susan S Bean Krista K Maecker Holden T HT Utz Paul J PJ James Judith A JA

JCI insight 20190124 2

Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or EL ...[more]

PMID: 30674728

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Project description:ImportanceAnti-double-stranded DNA (dsDNA) antibody has been reported to have a close relationship with systemic lupus erythematosus (SLE) flares and participates in the pathogenesis of lupus nephritis (LN) as well as causing damage to other organs. However, whether early use of mycophenolate mofetil (MMF) could prevent SLE flares is not clear.ObjectiveTo assess the efficacy and safety of MMF plus prednisone and hydroxychloroquine sulfate compared with prednisone and hydroxychloroquine sulfate alone in patients with SLE.Design, setting, and participantsThis investigator-initiated, multicenter, observer-blinded randomized clinical trial enrolled 130 participants aged 18 to 65 years and was conducted in 3 hospitals across China. Treatment-naive patients with newly diagnosed SLE, a high titer of anti-dsDNA antibody, and no major organ involvement were included. The study was started September 1, 2018, and the follow-up was completed September 30, 2021. Data were analyzed from December 1, 2021, to March 31, 2022.InterventionsPatients were randomized 1:1 to receive oral prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) (control group) or prednisone (0.5 mg/kg/d) and hydroxychloroquine sulfate (5 mg/kg/d) plus MMF (500 mg twice daily) (MMF group) for 96 weeks.Main outcomes and measuresThe primary outcome was the proportion of patients presenting with flares according to the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Flare Index. The secondary outcomes included the proportion with lupus low disease activity state at week 96, 36-Item Short Form Health Survey scores before and after treatment, proportion of adverse events (AEs), and changes in SLEDAI-2000 scores and prednisone doses.ResultsAmong 130 randomized patients (mean [SD] age, 34.5 [12.5] years; 112 [86.2%] women), 119 (91.5%) completed the follow-up. The risk of severe flare was significantly lower in the MMF group (7 of 65 [10.8%]) vs the control group (18 of 65 [27.7%]) (relative risk [RR], 0.39 [95% CI, 0.17-0.87]; P = .01). Additionally, 1 of 65 patients in the MMF group (1.5%) and 9 of 65 in the control group (13.8%) manifested LN (RR, 0.11 [95% CI, 0.01-0.85]; P = .008). Most common serious study drug-related AEs were infections (20 of 65 [30.8%] in the control group and 22 of 65 [33.8%] in the MMF group).Conclusions and relevanceThe findings of this randomized clinical trial suggest that MMF may reduce the rate of severe flare and lower the incidence of LN in patients with new-onset SLE and a high titer of anti-dsDNA antibody without major organ involvement.Trial registrationChinese Clinical Trial Registry: ChiCTR1800017540.

Project description:BackgroundMycophenolate 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.MethodsThis 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.FindingsBetween 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%]).InterpretationsMycophenolate 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.FundingThe National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Project description:BackgroundSystemic lupus erythematosus (SLE) is a clinically and biologically heterogeneous autoimmune disease. We explored whether the deconvolution of whole blood transcriptomic data could identify differences in predicted immune cell frequency between active SLE patients, and whether these differences are associated with clinical features and/or medication use.MethodsPatients with active SLE (BILAG-2004 Index) enrolled in the BILAG-Biologics Registry (BILAG-BR), prior to change in therapy, were studied as part of the MASTERPLANS Stratified Medicine consortium. Whole blood RNA-sequencing (RNA-seq) was conducted at enrolment into the registry. Data were deconvoluted using CIBERSORTx. Predicted immune cell frequencies were compared between active and inactive disease in the nine BILAG-2004 domains and according to immunosuppressant use (current and past).ResultsPredicted cell frequency varied between 109 patients. Patients currently, or previously, exposed to mycophenolate mofetil (MMF) had fewer inactivated macrophages (0.435% vs 1.391%, p = 0.001), naïve CD4 T cells (0.961% vs 2.251%, p = 0.002), and regulatory T cells (1.858% vs 3.574%, p = 0.007), as well as a higher proportion of memory activated CD4 T cells (1.826% vs 1.113%, p = 0.015), compared to patients never exposed to MMF. These differences remained statistically significant after adjusting for age, gender, ethnicity, disease duration, renal disease, and corticosteroid use. There were 2607 differentially expressed genes (DEGs) in patients exposed to MMF with over-representation of pathways relating to eosinophil function and erythrocyte development and function. Within CD4 + T cells, there were fewer predicted DEGs related to MMF exposure. No significant differences were observed for the other conventional immunosuppressants nor between patients according disease activity in any of the nine organ domains.ConclusionMMF has a significant and persisting effect on the whole blood transcriptomic signature in patients with SLE. This highlights the need to adequately adjust for background medication use in future studies using whole blood transcriptomics.

Project description:Our recent data showed that signal transducers and activators of transcription 1 (STAT1), adenosine deaminase acting on RNA (ADAR), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine 10 (CXCL10) were significantly elevated in a systemic lupus erythematosus (SLE) cohort compared to healthy donors. High and low STAT1 subsets were identified in SLE patient visits. The present study analyzed the correlation of common treatments used in SLE with the levels of these biomarkers.Peripheral blood leukocytes were collected from 65 healthy donors and 103 SLE patients, of whom 60 had samples from two or more visits. Total RNA was isolated and analyzed for the expression of mRNA and microRNA using Taqman real-time polymerase chain reaction (PCR) assays. Relative expression of interferon signature genes, CCL2, and CXCL10 were determined by the ??CT method. Results were correlated with therapy using prednisone, mycophenolate mofetil, and hydroxychloroquine and analyzed by Wilcoxon/Kruskal-Wallis test and Fisher's exact test.CCL2 and CXCL10 were significantly higher in untreated patients compared to treated patients, however, in high STAT1 patient visits there is no significant difference between treated and untreated patients' visits. When comparing linear regression fits of interferon (IFN) score with CCL2 and CXCL10, untreated patients and high STAT1 patients displayed significantly higher slopes compared to treated patients. There was no significant difference between the slopes of high STAT1 and untreated patients indicating that CCL2 and CXCL10 were correlated with type-I IFN in high STAT1 patients similar to that in untreated patients. CCL2 and CXCL10 levels in the high STAT1 subset remained high in treated patient visits compared to those of the low STAT1 subset.Among the biomarkers analyzed, only CCL2 and CXCL10 showed significantly reduced levels in treated compared to untreated SLE patients. STAT1, CCL2, and CXCL10 are potentially useful indicators of therapeutic action in SLE patients. Further work is needed to determine whether high STAT1 levels convey resistance to therapies commonly used to treat SLE and whether STAT1 inhibitors may have therapeutic implication for these patients.

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Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients.

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Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients.

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