David I. Daikh

American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis

In the United States, approximately 35% of adults with Systemic Lupus Erythematosus (SLE) have clinical evidence of nephritis at the time of diagnosis; with an estimated total of 50–60% developing nephritis during the first 10 years of disease [1–4]. The prevalence of nephritis is significantly higher in African Americans and Hispanics than in Caucasians, and is higher in men than in women. Renal damage is more likely to develop in non-Caucasian groups [2–4]. Overall survival in patients with SLE is approximately 95% at 5 years after diagnosis and 92% at 10 years [5, 6]. The presence of lupus nephritis significantly reduces survival, to approximately 88% at 10 years, with even lower survival in African Americans [5, 6]. The American College of Rheumatology (ACR) last published guidelines for management of systemic lupus erythematosus (SLE) in 1999 [7]. That publication was designed primarily for education of primary care physicians and recommended therapeutic and management approaches for many manifestations of SLE. Recommendations for management of lupus nephritis (LN) consisted of pulse glucocorticoids followed by high dose daily glucocorticoids in addition to an immunosuppressive medication, with cyclophosphamide viewed as the most effective immunosuppressive medication for diffuse proliferative glomerulonephritis. Mycophenolate mofetil was not yet in use for lupus nephritis and was not mentioned. Since that time, many clinical trials of glucocorticoids-plus-immunosuppressive interventions have been published, some of which are high quality prospective trials, and some not only prospective but also randomized. Thus, the ACR determined that a new set of management recommendations was in order. A combination of extensive literature review and the opinions of highly qualified experts, including rheumatologists, nephrologists and pathologists, has been used to reach the recommendations. The management strategies discussed here apply to lupus nephritis in adults, particularly to those receiving care in the United States of America, and include interventions that were available in the United States as of April 2011. While these recommendations were developed using rigorous methodology, guidelines do have inherent limitations in informing individual patient care; hence the selection of the term “recommendations.” While they should not supplant clinical judgment or limit clinical judgment, they do provide expert advice to the practicing physician managing patients with lupus nephritis.

An Inactivating Point Mutation in the Inhibitory Wedge of CD45 Causes Lymphoproliferation and Autoimmunity

A model has been proposed for the regulation of CD45, and by homology other RPTPs, in which dimerization inhibits phosphatase activity through symmetrical interactions between an inhibitory structural wedge and the catalytic site. Here, we report the phenotype of mice with a single point mutation, glutamate 613 to arginine, that inactivates the inhibitory wedge of CD45. The CD45 E613R mutation causes polyclonal lymphocyte activation leading to lymphoproliferation and severe autoimmune nephritis with autoantibody production, resulting in death. Both homozygotes and heterozygotes develop pathology, indicating genetic dominance of CD45 E613R. The dramatic phenotype of CD45 E613R mice demonstrates the in vivo importance of negative regulation of CD45 by dimerization, supporting the model for regulation of CD45, and RPTPs in general.

Cutting Edge: Reversal of Murine Lupus Nephritis with CTLA4Ig and Cyclophosphamide

Cyclophosphamide (CTX) prevents progression of nephritis and prolongs survival in (NZB × NZW)F1 (B/W) mice and is used to treat humans with lupus nephritis. To compare the efficacy of CTLA4Ig with CTX and determine whether there is an incremental benefit to combining CTLA4Ig with CTX, we treated B/W mice with CTX, CTLA4Ig, or both agents. In mice with mild renal disease, treatment delayed the onset of proteinuria and prolonged survival in all groups. In mice with advanced renal disease, treatment with both agents reduced proteinuria in 71% of mice, whereas mice treated with either agent alone had no such improvement. Survival was also markedly improved among mice treated with both agents. Thus, combination treatment with CTX and CTLA4Ig is more effective than either agent alone in reducing renal disease and prolonging survival of B/W mice with advanced nephritis. This striking reversal of proteinuria is unprecedented in animal models of SLE.

Suppression of Disease in New Zealand Black/New Zealand White Lupus-Prone Mice by Adoptive Transfer of Ex Vivo Expanded Regulatory T Cells

An increasing number of studies indicate that a subset of CD4+ T cells with regulatory capacity (regulatory T cells; Tregs) can function to control organ-specific autoimmune disease. To determine whether abnormalities of thymic-derived Tregs play a role in systemic lupus erythematosus, we evaluated Treg prevalence and function in (New Zealand Black × New Zealand White)F1 (B/W) lupus-prone mice. To explore the potential of Tregs to suppress disease, we evaluated the effect of adoptive transfer of purified, ex vivo expanded thymic-derived Tregs on the progression of renal disease. We found that although the prevalence of Tregs is reduced in regional lymph nodes and spleen of prediseased B/W mice compared with age-matched non-autoimmune mice, these cells increase in number in older diseased mice. In addition, the ability of these cells to proliferate in vitro was comparable to those purified from non-autoimmune control animals. Purified CD4+CD25+CD62Lhigh B/W Tregs were expanded ex vivo 80-fold, resulting in cells with a stable suppressor phenotype. Adoptive transfer of these exogenously expanded cells reduced the rate at which mice developed renal disease; a second transfer after treated animals had developed proteinuria further slowed the progression of renal disease and significantly improved survival. These studies indicate that thymic-derived Tregs may have a significant role in the control of autoimmunity in lupus-prone B/W mice, and augmentation of these cells may constitute a novel therapeutic approach for systemic lupus erythematosus.

An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus.

OBJECTIVE To assess whether R788, an orally bioavailable small molecule inhibitor of spleen tyrosine kinase (Syk)-dependent signaling, could modulate disease in lupus-prone (NZB x NZW)F1 (NZB/NZW) mice via inhibition of Fc receptor (FcR) and B cell receptor signaling. METHODS R788 was administered to NZB/NZW mice before and after disease onset. Proteinuria, blood urea nitrogen levels, and autoantibody titers were examined periodically, and overall survival and renal pathologic features were assessed following long-term treatment (24-34 weeks). The distribution and immunophenotype of various splenic T cell and B cell subpopulations were evaluated at the time of study termination. Arthus responses in NZB/NZW mice pretreated with R788 or Fc-blocking antibody (anti-CD16/32) were also examined. RESULTS When R788 was administered prior to or after disease onset, it delayed the onset of proteinuria and azotemia, reduced renal pathology and kidney infiltrates, and significantly prolonged survival of lupus-prone NZB/NZW mice; autoantibody titers were minimally affected throughout the study. Dose-dependent reductions in the numbers of CD4+ activated T cells expressing high levels of CD44 or CD69 were apparent in spleens from R788-treated mice. Minimal effects on the numbers of naive T cells expressing CD62 ligand and total CD8+ T cells per spleen were observed following long-term drug treatment. R788 pretreatment resulted in reduced Arthus responses in NZB/NZW mice, similar to results obtained in mice pretreated with FcR-blocking antibody. CONCLUSION We demonstrate that a novel Syk-selective inhibitor prevents the development of renal disease and treats established murine lupus nephritis. These data suggest that Syk inhibitors may be of therapeutic benefit in human lupus and related disorders.

CTLA-4: a key regulatory point in the control of autoimmune disease

Summary: Chronic autoimmune disease in humans is the result of a failure to control autoreactive immune cells in the periphery. This control is largely achieved by inhibition of newly activated and memory cells. A number of negative immune regulatory pathways have been characterized. The cell surface coreceptor cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) has emerged as a critical attenuator of T‐cell activation and an essential component of the regulatory systems that serve to maintain peripheral tolerance. CTLA‐4 expression is induced on the surface of T cells after they have received a costimulatory signal from antigen‐presenting cells (APCs) via engagement of CD28 on the T‐cell surface. CTLA‐4 attenuates this costimulation by competing for CD28 ligands and through direct effects on APCs via the same ligands utilized by CD28. A large number of genetic association studies suggest that the CTLA‐4 gene is a locus of susceptibility to autoimmune disease. However, specific functional defects in the CTLA‐4 gene in patients have not been identified to date. Elucidating the role of CTLA‐4 in immune tolerance has also led to a number of therapeutic applications, particularly in the treatment of malignancy and autoimmune disease.

Treatment of Lupus Nephritis with Abatacept: The Abatacept and Cyclophosphamide Combination Efficacy and Safety Study

To assess the efficacy and safety of a 24‐week course of abatacept in the treatment of active lupus nephritis and to assess the potential of abatacept to induce “clinical tolerance,” defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy.

A randomized trial of stress management for the prevention of new brain lesions in MS

Objectives: This trial examined the efficacy of a stress management program in reducing neuroimaging markers of multiple sclerosis (MS) disease activity. Methods: A total of 121 patients with relapsing forms of MS were randomized to receive stress management therapy for MS (SMT-MS) or a wait-list control condition. SMT-MS provided 16 individual treatment sessions over 24 weeks, followed by a 24-week post-treatment follow-up. The primary outcome was the cumulative number of new gadolinium-enhancing (Gd+) brain lesions on MRI at weeks 8, 16, and 24. Secondary outcomes included new or enlarging T2 MRI lesions, brain volume change, clinical exacerbation, and stress. Results: SMT-MS resulted in a reduction in cumulative Gd+ lesions (p = 0.04) and greater numbers of participants remained free of Gd+ lesions during the treatment (76.8% vs 54.7%, p = 0.02), compared to participants receiving the control treatment. SMT-MS also resulted in significantly reduced numbers of cumulative new T2 lesions (p = 0.005) and a greater number of participants remaining free of new T2 lesions (69.5% vs 42.7%, p = 0.006). These effects were no longer detectable during the 24-week post-treatment follow-up period. Conclusions: This trial indicates that SMT-MS may be useful in reducing the development of new MRI brain lesions while patients are in treatment. Classification of evidence: This study provides Class I evidence that SMT-MS, a manualized stress management therapy program, reduced the number of Gd+ lesions in patients with MS during a 24-week treatment period. This benefit was not sustained beyond 24 weeks, and there were no clinical benefits. Trial registration: ClinicalTrials.gov, number NCT00147446.

Block and tackle: CTLA4Ig takes on lupus

Blockade of antigen nonspecific costimulatory signals is a promising approach for the treatment of autoimmune diseases including systemic lupus erythematosus (SLE). CTLA4Ig, an antagonist of the CD28/B7 costimulatory interaction, effectively prevents SLE onset in several murine models and, when used in combination with cyclophosphamide, can induce remission of active SLE nephritis. In this review we describe the known mechanisms of action of CTLA4Ig both in normal immunity and in autoimmune disease models and address issues about its activity that still need to be resolved. We discuss the preclinical use of CTLA4Ig in murine SLE models and the rationale for a clinical trial in SLE patients.

The CD28-B7 costimulatory pathway and its role in autoimmune disease.

The activation of naive CD4+ T cells requires two discrete signals: a signal delivered by the T cell receptor following recognition of antigen and an accessory signal transduced when costimulatory receptors interact with their ligands. Particularly important in the development of an immune response to foreign antigens is the T cell molecule CD28, which delivers a potent costimulus when engaged by ligands, B7‐1 and B7‐2, on antigen‐presenting cells. It is interesting that blockade of B7 molecules, which disrupts interactions with CD28 and prevents delivery of the CD28 costimulus, also alters the immune responses to self antigens and prevents the development of clinical disease in murine models of systemic and organ‐specific autoimunity. Herein we review the roles of CD28 and its B7 ligands in the pathogenesis of autoimmunity, discuss efforts to treat animal models of autoimmunity by modifying the CD28 signal, and consider the mechanisms by which manipulation of the CD28 signal alters the course of experimental autoimmune disease. J. Leukoc. Biol. 62: 156–162; 1997.