Natasha Jordan

Rituximab in the treatment of resistant lupus nephritis: therapy failure in rapidly progressive crescentic lupus nephritis.

Objective *Deceased. The objective of this paper is to report the clinical outcome of B cell depletion therapy in 18 patients with refractory lupus nephritis (LN). Methods Eighteen patients received rituximab on an open-label basis with prospective evaluations. All patients had renal disease refractory to conventional immunosuppressive therapy, including intravenous cyclophosphamide (CyC). All patients fulfilled the revised ACR classification criteria for SLE. Rituximab was given as 2 × 1 g infusions with 500 mg iv CyC and 500 mg iv methylprednisolone, two weeks apart. Complete remission (CR) of nephritis at six months was defined as normal serum creatinine and serum albumin levels, inactive urine sediment, and proteinuria < 0.5 g/day; partial remission (PR) was defined as a ≥50% improvement in all renal parameters that were abnormal at baseline. Clinical response was assessed by the British Isles Lupus Assessment Group (BILAG) score pre- and post-rituximab treatment, and efficacy was recorded by extent and duration of B lymphocyte depletion (normal range 0.100–0.500 × 109/l). Follow-up data were collected at six months, one year post-treatment and at the most recent clinic visit. Results At six months, 11/18 patients reached renal CR and two of 18 PR. The mean global BILAG scores for responders decreased from 15 (SD 10) to 5 (SD 3), and a total of ten A scores disappeared. Five patients failed to show complete or partial renal response despite peripheral B lymphocyte count depletion, and progressed to end-stage renal failure (ESRF) and dialysis. Four of these patients had severe proliferative, crescentic nephritis, of whom three had Class IV-G, one Class III and one late membranous glomerulonephritis. One patient died six years after rituximab therapy from overwhelming sepsis while on long-term haemodialysis. Conclusion Rituximab therapy achieved a response in 13/18 patients with refractory LN. However, in patients with rapidly progressive crescentic LN, when there is already evidence of significant renal impairment, rituximab therapy may not prevent progression to ESRF and dialysis. Our data also suggest that severe Class IV-G LN may be associated with a poor response to therapy.

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.

Novel therapeutic agents in clinical development for systemic lupus erythematosus

Conventional immunosuppressive therapies have radically transformed patient survivalin systemic lupus erythematosus (SLE), but their use is associated with considerabletoxicity and a substantial proportion of patients remain refractory to treatment. Amore comprehensive understanding of the complexity of SLE immunopathogenesis hasevolved over the past decade and has led to the testing of several biologic agents inclinical trials. There is a clear need for new therapeutic agents that overcome theseissues, and biologic agents offer exciting prospects as future SLE therapies.An array of promising new therapies are currently emerging or are under developmentincluding B-cell depletion therapies, agents targeting B-cell survival factors,blockade of T-cell co-stimulation and anti-cytokine therapies, such as monoclonalantibodies against interleukin-6 and interferon-α.

Association of Thrombotic Microangiopathy and Intimal Hyperplasia With Bleeding Post–Renal Biopsy in Antiphospholipid Antibody–Positive Patients

Renal biopsy remains the gold standard investigation for both diagnostic and prognostic purposes in the clinical management of lupus nephritis. However, it is not without potentially significant complications. The objectives of this study were to determine the rate of significant bleeding post–renal biopsy in patients with lupus nephritis and to identify risk factors associated with hemorrhagic complications.

Systemic lupus erythematosus

ABSTRACT Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease that is highly heterogeneous in its presentation. This can pose significant challenges for physicians responsible for the diagnosis and treatment of such patients. SLE arises from a combination of genetic, epigenetic and environmental factors. Pathologically, the disease is primarily driven by loss of immune tolerance and abnormal B- and T-cell function. Major organ involvement may lead to significant morbidity and mortality. Classification criteria for SLE have been developed largely for research purposes; however, these are also widely used in clinical practice. Antinuclear antibodies are the hallmark serological feature, occurring in over 95% of patients with SLE at some point during their disease. The mainstay of treatment is antimalarial drugs such as hydroxychloroquine, combined with corticosteroids and conventional immunosuppressive drugs. An increasing understanding of pathogenesis has facilitated a move towards the development of targeted biologic therapies, with the introduction of rituximab and belimumab into clinical practice.

Increased risk of vascular complications in Takayasu’s arteritis patients with positive lupus anticoagulant

Objectives: Previous studies have shown antiphospholipid antibodies (aPL) to be prevalent in primary systemic vasculitides; however, the possible clinical impact of aPL positivity in such patients has not been explored in depth. The aims of this study were to determine the prevalence of aPL in patients with Takayasu’s arteritis (TA) and to ascertain whether aPL positivity was predictive of a worse clinical outcome in TA. Method: Clinical data were collected retrospectively on 22 TA patients over an 11-year period. Data collected included the presence of lupus anticoagulant (LA) and immunoglobulin (Ig)G and IgM anticardiolipin antibody (aCL) titres. Adverse clinical outcomes included cerebrovascular accident (CVA), transient ischaemic attack (TIA), loss of vision, vascular lesions (carotid, femoral, renal, coronary, or other vessels) requiring stenting, angioplasty, or other surgical intervention, aortic valve replacement, end-stage renal failure or death. Results: Persistently positive aPL or a concurrent diagnosis of antiphospholipid syndrome (APS) was found in 45% (n = 10) of TA patients while 55% (n = 12) had TA alone. LA was present in a significant proportion of TA patients with aPL (p = 0.002). Vascular complications occurred in 70% (n = 7) of TA patients with aPL and in 25% (n = 3) of TA patients without aPL (p = 0.035). LA was associated with a higher prevalence of vascular complications. Conclusions: Persistently positive aPL are present in a significant proportion of TA patients. This study shows that vascular complications and need for intervention are more prevalent in TA patients with aPL, particularly those with LA. Prospective studies are needed to determine the long term prognosis in such patients.

Key issues in the management of patients with systemic lupus erythematosus: latest developments and clinical implications.

Systemic lupus erythematous (SLE) is a chronic multisystem disease with significant associated morbidity and mortality. A deeper understanding of the pathogenesis of SLE has led to the development of biologic agents, primarily targeting B cells and others inhibiting costimulatory molecules, type I interferons and cytokines such as interleukin-6. Several of these agents have been studied in clinical trials; some have shown promise while others have yielded disappointing results. Economic and regulatory issues continue to hamper the availability of such therapies for SLE patients. With increasing recognition that recurrent flares of disease activity lead to long-term damage accrual, one of the most important recent developments in patient management has been the concept of treat-to-target in SLE while minimizing patient exposure to excessive corticosteroid and other immunosuppressive therapy. This article reviews these key issues in SLE management, outlining recent developments and clinical implications for patients.

Progress with the use of monoclonal antibodies for the treatment of systemic lupus erythematosus.

In recent years, significant progress has been made in the use of monoclonal antibodies in the treatment of systemic lupus erythematosus (SLE). Advances in our understanding of the complexity of SLE immunopathogenesis have led to the testing of several biologic agents in clinical trials. Monoclonal therapies currently emerging or under development include B-cell depletion therapies, agents targeting B-cell survival factors, blockade of T-cell co-stimulation and anticytokine therapies. Issues remain, however, regarding clinical trial design and outcome measures in SLE which need to be addressed to optimize translation of these promising therapies into clinical practice.

Dacryoadenitis and Diffuse Orbital Inflammation: Unusual First Presentations of Churg-Strauss Syndrome

Churg-Strauss syndrome (CSS) is a rare form of vasculitis involving small-to medium-sized blood vessels. CSS typically affects blood vessels of the lungs, gastrointestinal system, and peripheral nerves, but can also involve the heart, skin and kidneys. Here we present two CSS patients presenting with unusual ocular manifestations. Although ophthalmic complications remain relatively uncommon in vasculitides such as Churg-Strauss syndrome, these conditions should be considered in patients presenting with ocular manifestations and concurrent ear, nose and throat symptoms, arthralgia or with positive ANCA and eosinophilia.

Efficacy, pharmacokinetic and pharmacodynamic profile of belimumab for systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a severe autoimmune disease and a sizeable proportion of patients remain refractory to currently available immunosuppressive agents. The burden of uncontrolled disease is significant as disease flare and persistent inflammation lead to long-term damage accrual and increased morbidity. Belimumab, a humanized monoclonal antibody that inhibits B-lymphocyte stimulator (BLyS), is the first drug to be approved by the US FDA for the treatment of SLE in 50 years. Areas covered: In this review, we provide an overview of novel therapeutic agents under development for the treatment of SLE, a description of the pharmacodynamic and pharmacokinetic properties of belimumab, evidence of efficacy of belimumab as demonstrated in clinical trials, safety and tolerability data and a summary of ongoing clinical trials of belimumab in SLE. This information was amassed following a comprehensive MEDLINE and Cochrane library search. Ongoing clinical trial information was obtained from ClinicalTrials.gov. Expert opinion: Two, large Phase III trials have demonstrated the clinical efficacy of belimumab in musculoskeletal, mucocutaneous, haematologic and constitutional features of SLE. Patients with severe disease manifestations such as lupus nephritis and CNS disease were excluded from these trials and hence the role of belimumab in the overall management of SLE has yet to be established. Studies in lupus nephritis are ongoing.