Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date.

Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-ß and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab.

Advances in the treatment of systemic lupus erythematosus: From back to the future, to the future and beyond.

There have been many advances in the diagnosis and therapeutic management of systemic lupus erythematosus (SLE) over the past decades. Following more than eleven centuries of therapeutic uncertainty, the discovery of the therapeutic properties of glucocorticoids is without any doubt one of the most significant advance in the field of autoimmune diseases. The many progresses made by rapidly growing chemical industry of the 19th century chemistry have allowed the identification of valuable therapeutic compounds such as anti-malarials, cyclophosphamide, azathioprine, cyclosporine and later mycophenolate mofetil, which have all profoundly changed the face of the disease. A very visible consequence of this is the profound improvement in the prognosis of the disease, with 10-year survival rates of more than 90% in most dedicated centres. Following the development of biotherapies in rheumatoid arthritis, the late 20th century has slowly opened a new era for the treatment of SLE, that of targeted therapies. With the approval of belimumab in 2011 and 74 targeted therapies in clinical development, we may expect great changes in the therapeutic management of SLE. Those molecules target inflammatory cytokines or chemokines and their receptors, B cells or plasma cells, intracellular signalling pathways, B/T cells co-stimulation molecules, interferons, plasmacytoid dendritic cells, as well as various other targets of interest. Current challenges are now slowly shifting from whether some new drugs will be available to how to select the most adequate drug (or drug combination) at the patient-level.

The pipeline of targeted therapies under clinical development for primary Sjögren's syndrome: A systematic review of trials.

To date, no immunomodulatory drug has proved efficacious in primary Sjögren's syndrome (pSS). In pSS, difficulties in drug efficacy assessment is related to the large spectrum of clinical involvements (glandular/extraglandular involvement), to the lack of correlation between symptoms of dryness and glandular function assessed by objective measurements, as well as between symptoms and systemic complications of the disease. Severe organ manifestations are generally treated by off-label therapies in accordance with current practice and guidelines for Systemic Lupus Erythematosus or other connective-tissue diseases. Despite a much greater understanding of the pathogenesis of pSS, modern drug development has resulted in no approval of therapy so far. In this study, we performed a systematic review of all targeted therapies under clinical development in pSS, in 17 main online registries of clinical trials. Our search identified 264 trials, from which 25 targeted therapies for pSS were included. The molecules under current clinical development for pSS target B cells (n = 4), T cells or T/B cells costimulation (n = 5), inflammatory cytokines or chemokines and their receptors (n = 5), intracellular signalling pathways (n = 7) and various other targets identified in pSS (n = 4). The current drug development pipeline in pSS may lead to valuable strategies for the treatment of this currently difficult-to-treat disease.

10 most important contemporary challenges in the management of SLE.

From a 1-year survival of less than 50% before the discovery of glucocorticoids to over 90% at 10 years in most dedicated centres, the spectrum of SLE has profoundly evolved. Despite this improvement, several major challenges currently remain. The aim of this review is to analyse what are, according to us, the 10 most important contemporary challenges in the management of SLE. Among those are the need to treat to target to favour disease remission (or low disease activity), limit the use of glucocorticoids, derive more comprehensive tools for the evaluation of disease activity, develop more effective drugs (yielding successful trials), dissect the heterogeneity of the disease both at the molecular and genetic levels, identify relevant biomarkers for individualised treatment, manage fertility and pregnancy, tackle comorbidities such as cardiovascular risk, the prevention of infections and osteoporosis, improve the network of care (from the patients' perspective), and favour a holistic approach (integrating fatigue, adherence to treatment, physical activity). Altogether, these 10 contemporary challenges in SLE may be considered as a roadmap for those involved in the daily care of patients with SLE, as well as for researchers who may wish to contribute to an improved management of this rare and complex disease.

The 2018 pipeline of targeted therapies under clinical development for Systemic Lupus Erythematosus: a systematic review of trials.

Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials. The search yielded a total of 1140 trials, from which we identified 74 targeted therapies for SLE. Those treatments target inflammatory cytokines, chemokines, or their receptors (n = 17), B cells or plasma cells (n = 17), intracellular signalling pathways (n = 10), T/B cells costimulation molecules (n = 8), interferons (n = 7), plasmacytoid dendritic cells (pDC) (n = 3), as well as various other targets (n = 12). Not all these candidate drugs will reach phase III, but the broad spectrum of drugs being investigated may satisfy the urgent need for improved lupus medications. The identification of biomarkers that would allow adequate prediction of response-to-therapy remains high, but when solved will allow a more rationale selection of the optimal pharmacological agent at the patient level.