Therapeutic effect of retinoic acid in lupus nephritis

Lupus nephritis is a major cause of morbidity and mortality among patients with systemic lupus erythematosus (SLE). In these patients, treatment with immunosuppressive agents can significantly improve the outcome of lupus nephritis. However, these agents have severe adverse reactions and some patients are refractory to those therapies. Retinoids, a group of natural and synthetic derivatives of vitamin A, play important regulatory roles of cellular proliferation, differentiation and apoptosis. They have been used for the treatment of acute promyelocytic leukemia and inflammatory disorders such as psoriasis and acne. It has also been shown that retinoids have therapeutic effects in various animal models of kidney disease, including lupus nephritis. Based on these findings, retinoids are a promising agent for the treatment of lupus nephritis. We studied the clinical effects of retinoid therapy in patients with lupus nephritis. In open clinical trial, 7 patients with active lupus nephritis that was refractory to steroid therapy were studied. In all these patients, retinoid was added to the immunosuppressive therapy and its therapeutic effects were evaluated. As a result, 4 out of 7 patients showed improvement of the clinical symptoms and laboratory findings, including urinary protein and anti-dsDNA antibody levels. No important adverse effects of ATRA therapy were observed in all patients. Thus, retinoids might be indicated in cases of lupus nephritis that are refractory to conventional immunosuppressive therapy.     

Successful treatment of refractory thrombocytopenia with mycophenolate mofetil in a patient with systemic lupus erythematosus

While mild thrombocytopenia in systemic lupus erythematosus (SLE) is frequently seen in the context of active disease, severe thrombocytopenia causing significant bleeding is not that common. Corticosteroids are considered the first line therapy for severe thrombocytopenia in SLE. Second-line therapeutic agents or splenectomy have been reported to be effective for patients who fail to respond to steroids or those who require moderate doses of steroids to maintain the platelet counts. Recent randomized controlled studies have shown that mycophenolate mofetil (MMF) is an efficacious and safe therapeutic agent in patients with proliferative forms of lupus nephritis. However, little information has been available regarding the role of MMF in the treatment of immune thrombocytopenia complicated with SLE. Hereby I describe a patient with SLE in whom thrombocytopenia was refractory to corticosteroids, intermittent intravenous cyclophosphamide, azathioprine, cyclosporine, intravenous gamma globulin, danazol, and splenectomy, and whose platelet counts eventually normalized during therapy with MMF. In this patient, thrombocytopenia is initially thought to be associated with active SLE involving major organ. However, after immunosuppressive agents were given, the refractory nature of thrombocytopenia seems to be an isolated phenomenon, independently of SLE activity.     

SLE and infections

Infections are common in systemic lupus erythematosus (SLE), and remain a source of mortality. The types of infections (such as pneumonia, urinary tract infection, cellulitis, and sepsis) in SLE patients are similar to the general population and include the same pathogens (Gram-positive and Gram-negative). SLE patients may also develop opportunistic infections, especially when treated with immunosuppressive agents. As a high-risk population, identification and treatment of chronic infections such as tuberculosis, hepatitis B, or human immunodeficiency virus (HIV), are important prior to the institution of immunosuppression to prevent reactivation or exacerbation of the infection. A common caveat is to distinguish between a lupus flare and an acute infection; judicious use of corticosteroids and cytotoxic drugs is critical in limiting infectious complications. The risk factors associated with susceptibility to disease include severe flares, active renal disease, treatment with moderate or high doses of corticosteroids and/or immunosuppressive agents, and others. Genetic factors (complement deficiencies, mannose-binding lectin, Fcgamma III, granulocyte macrophage colony-stimulating factor [GM-CSF], osteopontin) may predispose certain SLE patients to develop infections. Parameters including C-reactive protein (CRP) and adhesion molecules may help to differentiate an infectious disease from an exacerbation of the disease. Finally, the mechanism of molecular mimicry by specific microbial agents may play a role in the induction of SLE.     

Molecular targets and their regulation in systemic lupus erythematosus

In the past 40 years, prognosis for patients with systemic lupus erythematosusu(SLE) has improved, and 10-year survival now becomes approximately over 95%. This may be due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Although the prognosis of SLE itself improved a lot, still the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease such as type IV lupus nephritis and CNS involvement, etc. To overcome these problems, various therapeutic approaches have been newly developed based on the understanding of molecular mechanisms involved in the pathogenesis of SLE. In this paper, usefulness of treatments targeting molecules that are strongly associated with immune disorders in lupus patients will be discussed.     

造血干细胞移植治疗系统性红斑狼疮的进展

系统性红斑狼疮是一种病因未明的自身免疫性疾病,基本上由自身抗体和免疫复合物介导致病.随着医学在基因水平上不断发展,对于重症SLE不能耐受传统疗法,HSCT目前已是公认的潜在治疗手段之一.从报道HSCT治疗严重AID至今,大约有20个国家的700个患者接受了临床Ⅰ/Ⅱ试验.研究认为,大剂量免疫抑制和移植后免疫重建可能是使SLE缓解的机制.经过10年的临床试验,国内对HSCT治疗手段不断成熟,以北京协和医院为首.虽有明显改善SLE病情,但随诊时期不长,仍存在着许多需要进一步解决的问题,HSCT给予那些难治的其他疗法无效的患者提供了"补救疗法",是否更有效,仍需要进一步进行随机化控制实验.     

Systemic Lupus Erythematosus, Progressive Multifocal Leukoencephalopathy, and T-CD4+ Lymphopenia

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by the reactivation of JC virus and occurs in patients with severe primary or secondary immunosuppression. Recently, PML is becoming relevant in autoimmune disorders, particularly in patients treated with biologic agents. However, systemic lupus erythematosus (SLE) appears to be associated with susceptibility to PML that cannot be entirely explained by the immunosuppressive therapy. The authors present two patients with the diagnosis of SLE and PML: One had a heavy immunosuppressive therapy history, and the other had never experienced biologic or cytotoxic therapeutics. Both patients had a profound T-CD4+ lymphopenia during their clinical history. These two cases emphasize the importance of CD4+ lymphopenia in SLE patients with and without immunosuppressors regarding opportunistic infections.     

Use of plasmapheresis in therapy of systemic lupus erythematosus: a controlled study

The effectivity of a combination of various plasma exchange regimens in combination with immunosuppressive medication consisting of corticosteroids and cyclophosphamide was tested in patients with severe systemic lupus erythematosus (SLE) the symptoms of which were found to be refractory to conventional immunosuppressive treatment administered orally. The patients were then submitted in a controlled manner to the following treatment modalities: 1. consecutive plasmapheresis (plasma exchanges every 2 to 3 days during a period of 2 to 3 weeks) with a continuation of immunosuppressive therapy administered orally; 2. chronic intermittent treatment (once per week) with parallel immunosuppression; 3. 2 plasmaphereses followed by an i.v. cyclophosphamide bolus. Only the third approach resulted in a stable and persistent clinical and serological improvement of disease activity.     

Murine chronic graft-versus-host disease as a model of systemic lupus erythematosus: effect of immunosuppressive drugs on disease development.

The effect of a number of drugs commonly used to treat the more severe exacerbations of the autoimmune disease systemic lupus erythematosus (SLE) in humans has been investigated in the murine chronic graft-versus-host (GVH) induced model of lupus. This was undertaken in order to determine the value of this model for the investigation of immunomodulant drugs, with particular regard to the reproducibility of disease induction and methods of monitoring disease progression. The drugs were azathioprine, cyclophosphamide, cyclosporin A and dexamethasone. All of these, except for azathioprine, reduced disease severity, assessed as the development of lupus nephritis. Anti-ssDNA autoantibodies were also reduced in titre in the dexamethasone-treated group. Overall, these findings, combined with the reproducible induction of disease seen in this model, support the use of chronic GVH disease as a model for SLE and show that the induced disease can be ameliorated by drugs effective in the treatment of SLE in humans.     

Management of systemic lupus erythematosus in Chinese patients

Systemic lupus erythematosus (SLE) is a worldwide disease with prevalence figures ranging from nine to 130 per 100,000 individuals. SLE appears to be more prevalent in certain ethnic groups, such as the African–Americans, African–Caribbeans and Asians. The prevalence of SLE in Hong Kong Chinese was estimated to be 59 out of 100,000 (104/100,000 among women), which is mid-way between that of the Caucasians and African–Americans. Certain organ manifestations, such as lupus nephritis, are more common in Chinese than Caucasians. A recent prospective study reported that the cumulative incidence of renal disease within 5 years of diagnosis of SLE in Chinese patients was 60%. Despite the improvement in survival of SLE in the past few decades, manifestations that are refractory to conventional therapies and treatment related complications are still major challenges in the management of SLE. Novel-therapeutic modalities for SLE should aim at targeting more specifically the immunopathogenetic pathways to achieve higher efficacy and reduce short- and long-term therapy-related toxicities. This review summarizes the management strategies and novel therapeutic modalities in SLE.     

Clinical usefulness of the Crithida luciliae test for antibodies to native DNA.

The Crithidia luciliae assay (CL-IF) for antibodies to native DNA was found to be significantly more sensitive and specific for systemic lupus erythematosus (SLE) than the Farr radioimmunoassay (RIA). High titers of antibodies to native DNA were seen exclusively in patients wtih SLE using the CL-IF test. The titers correlated with the activity of SLE and nephritis, in that the highest titers occurred in patients with active disease and severe nephritis, the lowest in patients with inactive lupus and normal renal function. Favorable responses to therapy were associated with decreases in CL-IF titers. The CL-IF assay can detect complement-fixing antibodies to native DNA. Their presence correlated with the disease activity and nephritis in SLE patients. The simple and inexpensive CL-IF test could either replace the RIA in clinical laboratories or be used in conjunction with the RIA as a confirmatory test for antibodies to native DNA.     

Abnormal intracellular distribution of NFAT1 in T lymphocytes from patients with systemic lupus erythematosus and characteristic clinical features

Systemic lupus erythematosus (SLE) presents various clinical features; however, underlying mechanisms remain unclear. In the immunity of SLE, impaired T cell receptor (TCR) signaling and altered cytokine production are in the center of pathogenesis, although, little is known about NFAT (nuclear factor of activated T cells) in lupus T lymphocytes. TCR stimulation activates NFAT1 through Ca2+/calcineurin (Cn) pathway, facilitating nuclear translocation of NFAT1 from cytosol. Therefore, we investigated relationship of disease activity/features and intracellular NFAT1 localization in T lymphocytes from active lupus patients by fractionation. Results showed no significant relationship between disease activity and NFAT1 distribution. However, interestingly, we observed skewed NFAT1 distribution in pellet in patients with active lupus nephritis or pleuritis. In vitro cyclosporin A treatment suggested autonomously activated Ca2+/Cn pathway in lupus T lymphocytes. Considering these results, NFAT1 might be presenting the clinical heterogeneity in SLE.     

Belimumab for the treatment of systemic lupus erythematosus

Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management of SLE.     

Th1/Th2 balance of SLE patients with lupus nephritis

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that is characterized by the production of multiple autoantibodies and immune complex formation. Lupus nephritis, which has various histological patterns and variable clinical outcomes, is one of the most important complications of SLE. Although this pathogenetic mechanism in each histologically different type of nephritis remains unclear, recent findings in murine lupus elucidate an essential role for the Th1 cytokine in the development of diffuse lupus nephritis (DLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of lupus nephritis. Therefore the value of Th1/Th2 ratio of the peripheral CD4+ T cells in SLE patients could be a useful index to predict histopathology of lupus nephritis.     

Refractory lupus nephritis: When,why and how to treat

Refractory lupus nephritis indicates an inadequate response to lupus nephritis therapy. It implies persisting or worsening disease activity despite therapy, but the definition is complicated by the parameters of response, proteinuria and renal function, that do not discriminate clearly between activity and irreversible damage. Understanding the causes of refractory disease and developing treatment strategies is important because these patients are more likely to develop poor outcomes, especially end stage renal disease. This review explores current concepts and definitions of refractory disease and summarises treatment approaches that have been used in observational cohort studies and case series. We highlight the importance of optimising adherence to the prescribed immunosuppressive and supportive measures and avoidance of diagnostic delay. Treatment options include higher dose glucocorticoid, switching between cyclophosphamide and mycophenolate acid derivates, or addition of rituximab, the latter potentially in combination with belimumab. Less evidence supports extracorporeal treatment (plasma exchange or immunoadsorption), calcineurin inhibitors (cyclosporine A or tacrolimus), intravenous immunoglobulin and stem cell transplantation. Improvements in understanding what refractory disease is and how definitions can be integrated into treatment pathways has the potential to enhance lupus nephritis outcomes.     

Pathogenic role of anti-C1q autoantibodies in the development of lupus nephritis--a hypothesis

A substantial proportion of patients with systemic lupus erythematosus (SLE) develop renal inflammatory disease, so-called lupus nephritis (LN). LN is a severe complication of SLE which is strongly associated with the presence of autoantibodies against C1q, the first component of the complement system, and other self-antigens (i.e. against DNA and nucleosomes) as well. In this review, the authors focus on anti-C1q autoantibodies and interpret the available data in order to explain how LN may develop and how anti-C1q autoantibodies contribute to its pathogenesis.     

Down-regulation of CD72 and increased surface IgG on B cells in patients with lupus nephritis

The significance of both the acceleratory and inhibitory functions of the CD72 molecule was investigated among patients with systemic lupus erythematosus (SLE) during modification of B cell differentiation. Expression of the CD72 molecule and mRNA on B cells was decreased in SLE with lupus nephritis, while CD100 expression on both CD4+ T cells and CD8+ T cells was not significant in comparison with the controls. When the relationship between CD72 expression and other B cell markers was examined, decreased expression of CD72 was associated with differences in the stage of differentiation. In patients with decreased expression of CD72, switching to IgG was evident, and the disease stage was started to severe. In patients with lupus nephritis, the decreased expression of CD72 was related to class switching on B cells, suggesting that CD72 is a useful marker for determining class switching of B cells in lupus nephritis.     

Murine lupus strains differentially model unique facets of human lupus serology

Systemic lupus erythematosus (SLE) is a polygenic autoimmune disease characterized by the production of anti-nuclear autoantibodies that lead to subsequent end organ damage. Previous array-based studies in patients with SLE have shown that high immunoglobulin (Ig)G anti-nuclear autoantibody reactivity was associated with severe renal lupus, whereas IgM polyreactivity was associated with less severe disease. To ascertain how different murine lupus strains recapitulate these different autoantibody profiles seen in patients, serum from New Zealand black (NZB)/NZ white (W) F(1), Murphy Roths large (MRL)/lpr, NZ mixed (M)2410 and BXSB strains were compared using a comprehensive array-based screen. The array results were verified using enzyme-linked immunosorbent assays (ELISAs). Serum from MRL/lpr mice exhibited high levels of IgG anti-nuclear antibodies as well as anti-glomerular antibodies and variable levels of antibodies to myosin, Matrigel and thyroglobulin. Elevated anti-nuclear IgG antibodies were associated with severe nephritis in this strain. In contrast, NZM2410 mice exhibited lower IgG autoantibody levels with less severe nephritis but a significantly higher polyreactive IgM autoantibody profile. ELISA analysis confirmed these results. The NZB/NZW F(1) and BXSB strains exhibited an intermediate serological profile. Hence, just as in patients with SLE, whereas strong IgG reactivity to nuclear antigens is associated with severe renal disease, a polyreactive IgM seroprofile is also less ominous in murine lupus.     

Biological and targeted therapies of systemic lupus erythematosus: evidence and the state of the art

Introduction: Systemic lupus erythematosus (SLE) is a multi-systemic disease characterized by an unpredictable disease course and periods of remission and flare, leading to organ damage and mortality. Novel biological agents are being developed (targeting the lymphocytes, accessory molecules and cytokines) that aim to enhance the therapeutic efficacy when combined with standard therapies.

Areas covered: This article updates recent data on the use of biological and targeted therapies in SLE.

Expert commentary: B cells remain the main target of development of novel therapeutics in SLE. Similar to the intravenous preparation, subcutaneous belimumab has been shown to be superior to placebo when added to the standard of care in SLE. However, two phase III trials of epratuzumab and blisibimod did not meet their primary endpoints. Recent data on the inhibition of type I interferons (anifrolumab) appear promising. Newer calcineurin inhibitors and combination strategies using conventional immunosuppressive agents are being tested in lupus nephritis. Finally, international groups are developing consensus definitions on disease remission and low disease activity state to explore the benefits of the treat-to-target strategy in SLE. Hopefully, the armamentarium for the treatment of SLE can be expanded in the near future, so that the longevity and quality of life of patients can be further improved.     

Two Cases of Refractory Thrombocytopenia in Systemic Lupus Erythematosus that Responded to Intravenous Low-Dose Cyclophosphamide

Treatment of thrombocytopenia in systemic lupus erythematosus (SLE) is considered in cases of current bleeding, severe bruising, or a platelet count below 50,000/µL. Corticosteroid is the first choice of medication for inducing remission, and immunosuppressive agents can be added when thrombocytopenia is refractory to corticosteroid or recurs despite it. We presented two SLE patients with thrombocytopenia who successfully induced remission after intravenous administration of low-dose cyclophosphamide (CYC) (500 mg fixed dose, biweekly for 3 months), followed by azathioprine (AZA) or mycophenolate mofetil (MMF). Both patients developed severe thrombocytopenia in SLE that did not respond to pulsed methylprednisolone therapy, and started the intravenous low-dose CYC therapy. In case 1, the platelet count increased to 50,000/µL after the first CYC infusion, and remission was maintained with low dose prednisolone and AZA. The case 2 achieved remission after three cycles of CYC, and the remission continued with low dose prednisolone and MMF.