Mycophenolic acid exposure and complement fraction C3 influence inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus

Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5′-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5′-monophosphate dehydrogenase activity in systemic lupus erythematosus patients. Methods Fifty systemic lupus erythematosus patients in remission maintenance phase (29 received mycophenolate mofetil [MMF+] and 21 did not [MMF−]) were enrolled. Median and interquartile range of dose of mycophenolate mofetil were 1500 and 1000–1500 mg/day, respectively. Stepwise multiple linear regression analysis was performed to assess the dependence between inosine 5′-monophosphate dehydrogenase activity and 25 predictor values including predose plasma concentrations of free mycophenolic acid and mycophenolic acid phenolic glucuronide. Results Median and interquartile range of predose total plasma concentrations of mycophenolic acid and mycophenolic acid phenolic glucuronide were 2.73 and 1.43–5.73 and 25.5 and 13.1–54.7 µg/mL, respectively. Predose inosine 5′-monophosphate dehydrogenase activity was significantly higher in MMF+ than MMF− patients (median 38.3 and 20.6 nmoL xanthosine 5′-monophosphate/g haemoglobin/h, P<0.01). The plasma concentration of free mycophenolic acid phenolic glucuronide, complement fraction C3 and body weight were significant predictors accounting for interindividual variability in the inosine 5′-monophosphate dehydrogenase activity (adjusted R2 = 0.52, P < 0.01) in a multivariate analysis. Conclusions Predose inosine 5′-monophosphate dehydrogenase activity was higher in systemic lupus erythematosus patients receiving mycophenolate mofetil therapy. Inosine 5′-monophosphate dehydrogenase activity may be determined by mycophenolic acid exposure and complement fraction C3 in systemic lupus erythematosus patients.

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Effective plasma concentrations of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in the remission-maintenance phase

Journal of Clinical Pharmacy and Therapeutics ◽

10.1111/j.1365-2710.2011.01269.x ◽

2011 ◽

Vol 37 (2) ◽

pp. 217-220 ◽

Cited By ~ 9

Author(s):

Y. Mino ◽

T. Naito ◽

K. Shimoyama ◽

N. Ogawa ◽

J. Kawakami

Keyword(s):

Systemic Lupus Erythematosus ◽

Mycophenolic Acid ◽

Lupus Erythematosus ◽

Plasma Concentrations ◽

Maintenance Phase ◽

Systemic Lupus ◽

Remission Maintenance

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AB0141 MYCOPHENOLATE MOFETIL, INHIBITOR OF INOSINE-5’-MONOPHOSPHATE DEHYDROGENASE, REGULATES DIFFERENTIATION, MATURATION AND FUNCTION OF HUMAN DENDRITIC CELL SUBSETS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3199 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1370.1-1371

Author(s):

M. Shigesaka ◽

T. Ito ◽

M. Inaba ◽

Y. Azuma ◽

S. Tsujimoto ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Mycophenolate Mofetil ◽

Human Blood ◽

Mycophenolic Acid ◽

Lupus Erythematosus ◽

Human Monocyte ◽

Type I ◽

Systemic Lupus ◽

And Function

Background:Systemic lupus erythematosus (SLE) is a heterogeneous disease in which excessive inflammation, autoantibodies, and complement activation lead to multisystem tissue damage. Plasmacytoid dendritc cells (pDCs) play a central role in the pathogenesis of SLE through dysregulated type I IFN production, together with activated myeloid DCs (mDCs), amplifying vicious spiral of autoimmune disorders(1). Therefore, control of the aberrant DC activation may provide an alternative treatment strategy against SLE.Objectives:Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks proliferation of B and T lymphocytes by inhibition of inosine-5-monophosphate dehydrogenase (IMPDH). In addition, although there is evidence indicating the immunosuppressive effects of MMF on human monocyte-derived dendritic cells(2.3), there are no reports showing its effects on human blood DC subsets. Here we focused on the effects of MMF on the functions of the blood pDCs and mDCs.Methods:We isolated human blood DCs from healthy donors using cell sorting(4) and examined the function of mycophenolic acid (MPA), which is metabolic products of MMF, on DC subsets in response to TLR-ligands and serum from patients with active SLE. Written informed consent was obtained from all healthy adult donors and SLE patients.Results:We found that therapeutic plasma concentration range of MPA down-regulated expression of CD40, CD80 and CD86 dose-dependently on mDCs and pDCs without inducing apoptosis, in response to R848(TLR7/8 agonist) and CpG2216(TLR9 agonist), respectively. Of note, MPA profoundly suppressed IL-12 production and STAT4 expression in the mDCs and IFN-α production and IRF7 expression in the pDCs(Fig 1). We also obserbed inhibition of nuclear translocation of IRF-7 in pDCs treated with MPA by confocal microscopy(Fig 2). Furthermore,we identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by human PBMCs.Conclusion:Our data suggest that MMF can drive a wedge into the vicious spiral of autoimmune disorders through regulating the function of not only lymphocyte but also DC subsets. Thus, we unveiled a part mechanism of the therapeutic ability of MMF against SLE.References:[1]A Plasmacytoid Dendritic Cells-Type I Interferon Axis is Critically Implicated in the Pathogenesis of Systemic Lupus Erythematosus. Int. J. Mol. Sci. 2015: 16, 14158-14170.[2]Mycophenolate mofetil inhibits differentiation, maturation and allostimulatory function of human monocyte-derived dendritic cells. Clin Exp Immunol. 2003;134:63-69.[3]Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells. Human Immunol. 2009;70: 692–700.[4]Miyamoto et al. Arthritis Research & Therapy 2010, 12:R87.Disclosure of Interests:None declared

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P108 Pharmacokinetics of mycophenolic acid for systemic lupus erythematosus in children

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.146 ◽

2019 ◽

Vol 104 (6) ◽

pp. e63.1-e63

Author(s):

D Zhang ◽

V Elie ◽

S Magreault ◽

I Melki ◽

V Baudouin ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Plasma Concentration ◽

Lupus Nephritis ◽

Mycophenolic Acid ◽

Lupus Erythematosus ◽

Interindividual Variability ◽

Plasma Concentrations ◽

Systemic Lupus ◽

Time Curve ◽

Concentration Time

BackgroundMycophenolate mofetil (MMF) is increasingly used in children with systemic lupus erythematosus (SLE). Monitoring of its active metabolite, mycophenolic acid (MPA), is performed for individual dosage adjustment of MMF and is based on determination of area under the plasma concentration-time curve (AUC12h) of MPA. The objective of this monocentric study is to describe the pharmacokinetics (PK) of MPA in paediatric patients with SLE or lupus nephritis.MethodsPatients with lupus treated by MMF between January 2009 and July 2018 were included. MPA plasma concentrations (T0, T0.5h, T1h, T2h, T3h, T8h and T12h) were determined by EMIT (enzyme-multiplied immunotechnique) and MPA AUC12h calculated according to trapezoid rule.ResultsTwenty-two patients were diagnosed with lupus at 11.5 ± 2.9 years. Clinical presentation was SLE (n=18) or isolated lupus nephritis (n=4). Treatments prior to MMF were steroids and/or immunosuppressants (endoxan, rituximab). Age at initiation of MMF (Cellcept®n=20, Myfortic®n=2) was 12.9 ± 2.6 years.PK of MPA was performed after 8.2 ± 14.8 months of treatment, under MMF dose of 840 ± 218 mg (577 ± 98 mg/m2). A large interindividual variability in MPA concentration-time profiles was observed with the following mean parameters: Cmax=4.60 ± 11.70 µg/mL, tmax=80 ± 77 min, trough plasma concentration (C0) = 2.30 ± 1.60 µg/mL and AUC0-12h=46.29 ± 17.39 µg*h/mL.ConclusionData on the PK of MPA in lupus children are limited. Our results show the high interindividual variability in MPA exposure after oral administration of MMF. Monitoring of exposure based on AUC in combination with immunological disease parameters will allow to individualise treatment to optimiseDisclosure(s)Nothing to disclose

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Beneficial effect of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil on survival and severity of glomerulonephritis in systemic lupus erythematosus (SLE)-prone MRLlpr/lpr mice

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.1999.00901.x ◽

1999 ◽

Vol 116 (3) ◽

pp. 534-541 ◽

Cited By ~ 55

Author(s):

JONSSON ◽

SVENSSON ◽

CARLSTEN

Keyword(s):

Systemic Lupus Erythematosus ◽

Mycophenolate Mofetil ◽

Beneficial Effect ◽

Lupus Erythematosus ◽

Inosine Monophosphate Dehydrogenase ◽

Systemic Lupus ◽

Inosine Monophosphate ◽

Monophosphate Dehydrogenase

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Mycophenolic Acid Exposure Optimization Based on Vitamin D Status in Children with Systemic Lupus Erythematosus: A Single-Center Retrospective Study

Rheumatology and Therapy ◽

10.1007/s40744-021-00324-w ◽

2021 ◽

Author(s):

Qiaofeng Ye ◽

Guangfei Wang ◽

Yidie Huang ◽

Jinmiao Lu ◽

Junqi Zhang ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Vitamin D ◽

Retrospective Study ◽

Mycophenolic Acid ◽

Lupus Erythematosus ◽

Acid Exposure ◽

Vitamin D Status ◽

Single Center ◽

Systemic Lupus

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POS0685 MYCOPHENOLATE MOFETIL IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS: FIVE-YEARS DRUG SURVIVAL IN RENAL AND NON-RENAL INVOLVEMENT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.925 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 588.2-588

Author(s):

G. Olivieri ◽

F. Ceccarelli ◽

F. Natalucci ◽

F. R. Spinelli ◽

C. Alessandri ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Mycophenolate Mofetil ◽

Disease Activity ◽

Lupus Erythematosus ◽

Treatment Duration ◽

Retention Rate ◽

Renal Involvement ◽

Joint Involvement ◽

Systemic Lupus ◽

Median Treatment

Background:The updated EULAR recommendations for the management of systemic lupus erythematosus (SLE) underline the use of Mycophenolate Mofetil (MMF) in the treatment of different disease related manifestations (1). Several randomized controlled trials have demonstrated the efficacy of MMF in lupus nephritis (LN) patients but only case series and open-labelled trials have analyzed the use of this drug in other than LN features. Moreover, no data are available about the MMF retention rate in a real-life setting.Objectives:The present study aims at evaluating the 5-years drug retention rate (DRR) of MMF in a large monocentric SLE cohort. Secondly, we investigated the influence of MMF in disease activity changes and chronic damage progression.Methods:We performed a longitudinal study including all the SLE patients (ACR 1997 criteria) starting MMF treatment in our Lupus Clinic. Data about indications, mean dosage, duration of treatment and reasons for drug withdrawal were registered. The DRR was estimated using the Kaplan–Meier method. Disease activity and chronic damage were assessed by SLE Disease Activity Index 2000 (SLEDAI-2K) and SLICC Damage Index (SDI), respectively.Results:The present analysis included 162 SLE patients (M/F 22/140, median age at the disease diagnosis 25.5 years, IQR 13). At the beginning of MMF treatment, we registered a median age of 34 months (IQR 21) and a median disease duration of 72 months (IQR 123). The most frequent indications for prescribing MMF were LN (101 patients, 62.3%) and musculoskeletal manifestations (39, 24.1%), followed by neuropsychiatric involvement (10, 6.2%), and others disease related manifestations (12, 7.4%; in particular skin involvement, hematological features, myositis, vasculitis). MMF was administered at a mean daily dosage of 2.1±0.6 grams; no differences in dosage were found between the different indications (p=ns).At the longitudinal analysis, we registered a median treatment duration of 30 months (IQR 55). Figure 1 reported data about DRR: in particular, at 60 months follow-up we observed a DRR of 61.1% for LN patients, which was similar to that registered for patients without renal involvement (NLN) (60.5%; p=ns). Interestingly, the DRR at 60 months was higher in the subgroup of patients treated for joint involvement (75.4%), even without reaching a statistically significant difference. During the observation period, 92 patients (59.2%) discontinued MMF (median treatment duration at discontinuation 25 months, IQR 35). Interestingly, the main cause of withdrawal was the achievement of persistent remission, observed in 20 patients (21.7%), followed by loss of efficacy (19 patients, 20.5%), drug intolerance and pregnancy planning (17 patients for both reasons, 18,4%). Furthermore, our analysis confirmed MMF efficacy, as demonstrated by the significant reduction in SLEDAI-2k values after 4, 12 and 24 months of treatment (p< 0.0001 for all the time-points in comparison with baseline). In addition, MMF resulted able to control chronic damage progression, as demonstrated by the lack of significant increase in SDI values (baseline: 0.6, IQR 1; last observation: 0.93, IQR 1; p=ns).Conclusion:The evaluation of a large SLE cohort demonstrated a good retention rate for MMF. In particular, our results demonstrated that MMF is also a safe and effective drug for SLE manifestation other than LN, in particular for joint involvement. Moreover, it is able to control disease activity and to prevent the progression of chronic damage.References:[1]Fanouriakis A et al. Ann Rheum Dis. 2019 Jun;78(6):736-745.Disclosure of Interests:None declared

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A patient with systemic lupus erythematosus and lupus nephritis: A 12-year follow-up

Vojnosanitetski pregled ◽

10.2298/vsp1108705j ◽

2011 ◽

Vol 68 (8) ◽

pp. 705-708

Author(s):

Natasa Jovanovic ◽

Jasmina Markovic-Lipkovski ◽

Stevan Pavlovic ◽

Biljana Stojimirovic

Keyword(s):

Systemic Lupus Erythematosus ◽

Nephrotic Syndrome ◽

Mycophenolate Mofetil ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Kidney Biopsy ◽

Immunosuppressive Drugs ◽

Systemic Lupus ◽

Younger Women ◽

The Right

Introduction. Systemic lupus erythematosus (SLE) is a chronic immunological disease causing a significant morbidity and mortality in younger women and involving several organs and systems, most often the kidneys, being consequently the incidence of lupus nephritis (LN) about 60%. Case report. We reported a 57 year-old patient with the diagnosed SLE in 1995. Pathohistological analysis of kidney biopsy revealed LN type V. The patient was treated with corticosteroid pulses and azathioprine during one year. A remission was achieved and maintained with prednisone, 15 mg daily. Nephrotic relapse was diagnosed in 2006 and the second kidney biopsy revealed recent kidney infarction due to extensive vasculitis. Soon, a cerebrovascul insult developed and CT-scan revealed endocranial infarctus. The patient was treated with corticosteroids and cyclophosphamide pulses (totally VI monthly pulses), and also with low-molecular heparine, anticoagulants and salicylates because of the right leg phlebothrombosis. After the pulses, the patient was adviced to take prednisone 20 mg daily and azothioprine 100 mg daily, and 6 months later mycophenolate mofetil because of persistent active serological immunological findings (ANA 1 : 320) and nephrotic syndrome. Mycophenolate mofetil was efficient in inducing and maintaining remission of nephrotic syndrome. Conclusion. The aim of LN treatment is to achieve and maintain remission, improve patients? outcome, reduce the toxicity of immunosuppressive drugs and the incidence of relapses. Mycophenolate mofetil was shown to be efficient in inducing and maintaining remission of nephrotic syndrome in the frame of LN.

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