Refractory lupus nephritis: When, why and how to treat

Kronbichler, Andreas; Brezina, Biljana; Gauckler, Philipp; Quintana, Luís F.; Jayne, David

doi:10.1016/j.autrev.2019.03.004

Cited by 62 publications

(46 citation statements)

References 94 publications

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“…In this study, we showed for the first time the feasibility and potential efficacy of iguratimod in LN management, with a 92.3% response rate at week 24. This response rate is comparable to that reportedly achieved by other therapies that have been investigated for treating refractory LN, including calcineurin inhibitors [9,10], rituximab [6][7][8], and stem cell transplantation [25].…”

Section: Discussionsupporting

confidence: 76%

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study

Kang

Yan

et al. 2020

Arthritis Res Ther

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Objectives: Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). Methods: We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/ partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. Results: The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0-10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. Conclusions: Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.

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Section: Discussionsupporting

confidence: 76%

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study

Kang

Yan

et al. 2020

Arthritis Res Ther

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“…On the other hand, caution has been raised by some authors who witnessed patients developing LN while undergoing therapy with BEL (24,25). However, a recent extensive review (26) of the treatment of refractory LN concludes that BEL-in combination with RTX, and possibly as monotherapy-will play a role. In the meantime, Glaxo Smith Kline, the manufacturer of Belimumab, has released a news outline that the phase 3 study of BEL in LN reached its primary endpoint (27).…”

Section: Discussionmentioning

confidence: 99%

Clinical Efficacy of Routinely Administered Belimumab on Proteinuria and Neuropsychiatric Lupus

et al. 2020

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Background and Objectives: Belimumab (BEL) is a monoclonal antibody approved for the treatment of active systemic lupus erythematosus (SLE) but not for lupus nephritis (LN) and neuropsychiatric systemic lupus erythematosus (NPSLE). We aimed to assess BEL's effects on these severe, potentially life-threatening manifestations. Methods: Retrospective observational cohort study using routine clinical data in a case series of patients with SLE receiving BEL. Results: Sixteen patients received BEL therapy for active SLE. Nine were excluded because they had no LN or NPSLE. Six suffered from LN, and one patient had NPSLE. All LN patients received BEL in addition to standard therapy including glucocorticoids, hydroxychloroquine, and mycophenolate mofetil in five cases, and tacrolimus in one case. Three patients with proteinuria >1,000 mg/g creatinine responded well (one complete, two partial renal responses); all other patients had decreasing proteinuria and a reduction in anti-dsDNA levels. The patient with NPSLE who had failed previous therapies had persistent clinical improvement of cutaneous and neuropsychiatric manifestations. There was one mild allergic reaction and one lower respiratory tract infection, but no other adverse events. One patient discontinued therapy due to a lack of improvement in clinical symptoms, another because of clinical remission. Conclusions: In our series, BEL led to a decrease of proteinuria in patients with proteinuria of more than 1,000 mg/g creatinine despite standard of care treatment, and led to a marked clinical improvement in one patient with NPSLE. No adverse events were observed. Routinely administered BEL shows clinical efficacy on non-approved manifestations, but careful patient selection is warranted.

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“…For example, the accumulated evidence thus far suggests that anti-TNF agents may have limited or no role in the treatment of SLE, although they showed success in RA patients. However, the biologic rituximab targeting CD20 molecules on B cells is effective in RA patients and may also have potential in SLE patients with severe and refractory lupus nephritis [89]. Similar examples can be found in treatment with csDMARDs, such as HCQ and MTX, in both SLE patients and RA patients.…”

Section: Clinical Analyses Of Blocking the Cd40-cd154 Axis In Humansmentioning

confidence: 99%

Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis

Lai

Luo

2019

Cells

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Full activation of T lymphocytes requires signals from both T cell receptors and costimulatory molecules. In addition to CD28, several T cell molecules could deliver costimulatory signals, including CD154, which primarily interacts with CD40 on B-cells. CD40 is a critical molecule regulating several B-cell functions, such as antibody production, germinal center formation and cellular proliferation. Upregulated expression of CD40 and CD154 occurs in immune effector cells and non-immune cells in different autoimmune diseases. In addition, therapeutic benefits have been observed by blocking the CD40-CD154 interaction in animals with collagen-induced arthritis. Given the therapeutic success of the biologics abatacept, which blocks CD28 costimulation, and rituximab, which deletes B cells in the treatment of autoimmune arthritis, the inhibition of the CD40-CD154 axis has two advantages, namely, attenuating CD154-mediated T cell costimulation and suppressing CD40-mediated B-cell stimulation. Furthermore, blockade of the CD40-CD154 interaction drives the conversion of CD4+ T cells to regulatory T cells that mediate immunosuppression. Currently, several biological products targeting the CD40-CD154 axis have been developed and are undergoing early phase clinical trials with encouraging success in several autoimmune disorders, including autoimmune arthritis. This review addresses the roles of the CD40-CD154 axis in the pathogenesis of autoimmune arthritis and its potential as a therapeutic target.

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Refractory lupus nephritis: When, why and how to treat

Cited by 62 publications

References 94 publications

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study

Clinical Efficacy of Routinely Administered Belimumab on Proteinuria and Neuropsychiatric Lupus

Targeting the CD40-CD154 Signaling Pathway for Treatment of Autoimmune Arthritis

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