High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis

Schaier, Matthias; Scholl, Christian; Scharpf, Dominik; Schmitt, Wilhelm H.; Schwenger, Vedat; Zeier, Martin; Sommerer, Claudia

doi:10.1093/ndt/gfv065

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…Infectious complications are the leading cause of death during the first year after disease onset [8][9][10]. Efforts have been made to reduce the immunosuppressive burden either through reducing cumulative immunosuppressive dose, performing therapeutic drug monitoring or through replacing commonly used medication by more disease-specific, less toxic agents [13,[19][20][21]. We aimed to investigate the impact of GC maintenance dose and duration on AAV patient outcomes with an emphasis on infectious complications.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis

Speer

Altenmüller-Walther

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et al. 2020

Rheumatol Int

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To study the impact of glucocorticoid maintenance dose and treatment duration on outcomes in patients with AAV (ANCA-associated vasculitis) with emphasis on infectious complications. A total of 130 AAV patients from two German vasculitis centers diagnosed between August 2004 and January 2019 treated with cyclophosphamide and glucocorticoids for induction therapy and glucocorticoids for maintenance therapy were retrospectively enrolled. We investigated the influence of glucocorticoid maintenance therapy on patient survival, time to relapse, kidney function, infectious complications and irreversible physical damage. The patients were divided into the following groups: patients treated according to the predefined reduction scheme (< 7.5 mg) or patients treated with glucocorticoids ≥ 7.5 mg after 6 months. Compared to patients receiving < 7.5 mg glucocorticoids after 6 months, patients receiving $$\ge $$ ≥ 7.5 mg had an increased rate of infectious episodes per patient (1.7 vs. 0.6; p < 0.001), including urinary tract infection (p = 0.007), pneumonia (p = 0.003), opportunistic pneumonia (p = 0.022) and sepsis (p = 0.008). Especially pneumonia during the first 24 months after disease onset [hazard ratio, 3.0 (95% CI 1.5 − 6.1)] led to more deaths from infection (p = 0.034). Glucocorticoid maintenance therapy after 6 months had no impact on relapse rate or patient survival and decline in kidney function was comparable. Glucocorticoid maintenance therapy with $$\ge $$ ≥ 7.5 mg after 6 months is associated with more severe infectious complications leading to an increased frequency of deaths from infection. Glucocorticoid maintenance therapy has no effect on time to relapse or patient survival and should therefore be critically revised throughout the aftercare of AAV patients.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis

Speer

Altenmüller-Walther

Splitthoff³

et al. 2020

Rheumatol Int

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“…The concentration range was reduced by 10-fold in subsequent experiments due to the potent inhibitory effects of MPA on ECFC in vitro . This raises concern that MPA at current patient therapeutic doses may possess potential vascular toxicity especially with the notable narrow therapeutic index of MPA and large intra- and inter-individual variation in both MPA plasma concentrations and levels of IMPDH activity [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Mycophenolic acid induces senescence of vascular precursor cells

Tarnawsky

Shelley

et al. 2018

PLoS ONE

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ObjectiveEndothelial dysfunction is central to the pathogenesis of many rheumatic diseases, typified by vascular inflammation and damage. Immunosuppressive drugs induce disease remission and lead to improved patient survival. However, there remains a higher incidence of cardiovascular disease in these patients even after adequate disease control. The purpose of this study was to determine the effect of mycophenolic acid (MPA), a commonly used immunosuppressive drug in rheumatology, on blood vessel or circulating endothelial colony forming cell number and function.MethodsWe tested whether mycophenolic acid exerts an inhibitory effect on proliferation, clonogenic potential and vasculogenic function of endothelial colony forming cell. We also studied potential mechanisms involved in the observed effects.ResultsTreatment with MPA decreased endothelial colony forming cell proliferation, clonogenic potential and vasculogenic function in a dose-dependent fashion. MPA increased senescence-associated β-galactosidase expression, p21 gene expression and p53 phosphorylation, indicative of activation of cellular senescence. Exogenous guanosine supplementation rescued diminished endothelial colony forming cell proliferation and indices of senescence, consistent with the known mechanism of action of MPA.ConclusionOur findings show that clinically relevant doses of MPA have potent anti-angiogenic and pro-senescent effects on vascular precursor cells in vitro, thus indicating that treatment with MPA can potentially affect vascular repair and regeneration. This warrants further studies in vivo to determine how MPA therapy contributes to vascular dysfunction and increased cardiovascular disease seen in patients with inflammatory rheumatic disease.

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“…[ 2 ] DMARDs, including mycophenolic acid, were administered for 2 months, but the wound healing response was very poor. Although mycophenolic acid might play a role in the treatment of anti-neutrophil cytoplasm antibody-associated systemic vasculitis, [ 6 ] we consider the mycophenolic acid therapy in our patient to be unsuccessful. The wounds continued to heal without mycophenolic acid post third dose of omalizumab, which indicated that the patient did not respond to mycophenolic acid.…”

Section: Discussionmentioning

confidence: 92%

Treatment of multiple refractory ankle ulcerations in thromboangiitis obliterans

Huang

Kuo

Chiu³

et al. 2018

Medicine

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Rationale:Thromboangiitis obliterans (TAOs, or Buerger's disease) present as a non-atherosclerotic segmental occlusive vasculitis within medium- and small-sized blood vessels. TAO frequently occurs in young adults and is associated with cigarette smoking. At present, there are no accurately defined treatments for TAO.Patient concerns:A 34-year-old Asian woman with a 20-year history of heavy cigarette smoking and recurrent, small, and self-limited lower limb ulcerations since adolescence, presented with persisting unhealed ulcerations on both ankles for 6 months. Her wound healing response was poor following the 2-month administration of colchicine, prednisolone, hydroxychloroquine, and mycophenolic acid.Diagnosis:The patient was diagnosed with TAO with hyperimmunoglobulin E and refractory ulcerations on her ankles.Interventions:The patient received monthly omalizumab (300 mg) and previous medications for 2 months and shifted to omalizumab and colchicine without mycophenolic acid and hydroxychloroquine because of onychomadesis, which was considered to be a possible adverse drug reaction.Outcomes:The wounds healed almost completely. The administration of omalizumab and colchicine will be continued until they the wounds are fully healed.Lessons:Mycophenolic acid has a limited function in TAO treatment, especially in cases of refractory skin ulcerations. Omalizumab can be a valuable treatment option for patients with TAO and hyperimmunoglobulin E.

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High interpatient variability in response to mycophenolic acid maintenance therapy in patients with ANCA-associated vasculitis

Abstract: Due to the highly variable response to maintenance therapy with MPA, PD drug monitoring is a new tool for detecting inadequate immunosuppression in AASV patients.

Cited by 12 publications

References 42 publications

Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis

Glucocorticoid maintenance therapy and severe infectious complications in ANCA-associated vasculitis: a retrospective analysis

Mycophenolic acid induces senescence of vascular precursor cells

Treatment of multiple refractory ankle ulcerations in thromboangiitis obliterans

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