Induction treatment of proliferative lupus nephritis with leflunomide                 combined with prednisone: a prospective multi-centre observational study

Wang, H. Y.; Cui, Taigen; Hou, F. F.; Ni, Zhaohui; Chen, X. M.; Lu, Fuming; Xu, Fei; Yu, Xueqing; Zhang, F. S.; Zhao, Xiaona; Zhao, Ming‐Hui; Wang, G. B.; Qian, Jie; Cai, Guangyan; Zhu, Tingting; Wang, Y. H.; Jiang, Zeying; Li, Y. N.; Mei, Changlin; Zou, Wan-zhong

doi:10.1177/0961203308089408

Cited by 101 publications

(81 citation statements)

References 25 publications

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“…27 Another trial compared efficacy and safety of leflunomide and CYC in 110 patients with biopsyproven diffuse-proliferative lupus nephritis. 28 Leflunomide was found to be equally effective as compared with CYC but caused the well known side effects. 28 It is unknown whether these side effects are leflunomide-specific or a result of DHODH inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…28 Leflunomide was found to be equally effective as compared with CYC but caused the well known side effects. 28 It is unknown whether these side effects are leflunomide-specific or a result of DHODH inhibition. The observation that leflunomide can induce cutaneous lupus may argue for drugspecific side effects rather than for DHODH inhibition.…”

Section: Discussionmentioning

confidence: 99%

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4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Kulkarni

Sayyed

Kantner

et al. 2010

The American Journal of Pathology

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Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/ week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal , dermal , and pulmonary SLE manifestations of MRL(Fas)lpr mice. However , even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts , which were significantly reduced in CYC-treated mice. Together , the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence , DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC. (Am J Pathol

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Kulkarni

Sayyed

Kantner

et al. 2010

The American Journal of Pathology

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“…Leflunomide, which is used in the treatment of rheumatoid arthritis, has been investigated in a clinical trial in China that compared its efficacy with intravenous CYC in patients with active proliferative LN, and the results showed comparable rates of complete remission (21 vs. 18%) and partial remission (52 vs. 55%) [64]. Infective complications and bone marrow suppression were recognized complications.…”

Section: Emerging Treatments In Asia and Concluding Remarksmentioning

confidence: 99%

Lupus Nephritis in Asia: Clinical Features and Management

Yap

Chan²

2015

Kidney Dis

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Background: Lupus nephritis (LN) is a common and severe organ involvement manifesting itself in systemic lupus erythematosus (SLE). There is a considerable difference in prevalence, severity, treatment response and outcomes between Asian LN patients and LN patients from other racial backgrounds. Summary: Asian SLE patients have a higher prevalence of LN than Caucasian SLE patients and often present with a more severe disease. Increasing data from genetic studies, accompanied by progress in high-throughput genotyping, have advanced our knowledge about genetic predispositions that might partly contribute to the clinical variations observed. Corticosteroids combined with either cyclophosphamide (CYC) or mycophenolic acid (MPA) is the current standard-of-care induction regimen for severe LN irrespective of race or ethnicity. However, the preference for MPA or CYC, and possibly the optimum dose for MPA, is influenced by the patient's origin. Also, there is an insufficient evidence base for reduced-dose intravenous CYC in Asian patients. Health economics and access to prompt diagnosis and treatment are still challenging issues in some Asian regions. The former represents a significant obstacle limiting the access of patients to MPA despite the proven efficacy of the drug as an induction agent and its superiority over azathioprine (AZA) in preventing disease flares when used for long-term maintenance immunosuppression. Calcineurin inhibitors such as tacrolimus deserve further investigation in view of their additional effect on podocytes by reducing proteinuria and the promising data from Asian patients. Despite considerable advances in the clinical management of LN over the past few decades with resultant improvements in patients' outcomes, there are still knowledge gaps and unmet clinical needs. Asia has made substantial contributions to the evidence base that guides clinical management and continues to offer invaluable opportunities for research pursuits. Key Messages: Treatment responses and clinical outcomes in Asian patients with LN compare favorably with patients from other parts of the world. The prevention and treatment of infective complications remain significant challenges in managing LN in Asia. Facts from East and West: (1) The prevalence of SLE is lower among Caucasians than other ethnicities. A higher prevalence is observed among Asians and African Americans, while the highest prevalence is found in Caribbean people. The prevalence of LN in Asian SLE patients is much higher than in Caucasians as well. However, the 10-year renal outcome and renal survival rate appear to be better in Asians. (2) Polymorphisms of genes involved in the immune response, such as Fcγ receptor, integrin alpha M, TNF superfamily 4, myotubularin-related protein 3 and many others, might be partly responsible for the differences in prevalence between the different ethnic groups. European ancestry was shown to be associated with a decrease in the risk of LN even after adjustment for genes most associated with renal disease. (3) Access...

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“…85 Other immunosuppressants like dihydroorotate dehydrogenase inhibitors add to the current choices but are still nonspecific. 86,87 However, lupus drug developers continue to search for new drugs that more specifically modulate the aberrant immunity in SLE with fewer side effects.…”

Section: Nonselective Immunosuppressantsmentioning

confidence: 99%

The Pathogenesis of Lupus Nephritis

Lech¹,

Anders

2013

Journal of the American Society of Nephrology

382

295

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Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.

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Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study

Cited by 101 publications

References 25 publications

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Lupus Nephritis in Asia: Clinical Features and Management

The Pathogenesis of Lupus Nephritis

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