Research – The Future

This site is intended for healthcare professionals as a useful source of information on the diagnosis, treatment and support of patients with lupus and related connective tissue diseases.


Research is the acquisition of new knowledge through systematic investigation to
establish facts and reach new conclusions. This chapter will address the main areas
of recent lupus research and discuss possible future advances.

Factors in the development of Lupus

A key advance in understanding the pathophysiology of lupus is elucidation of inflammatory pathways responsible for driving the disease process in lupus and designing drugs to target these pathways.

B-cell activating factor (BAFF), also known as B Lymphocyte Stimulator (BLyS), is a cytokine that belongs to the tumour necrosis factor (TNF) ligand family. It stimulates B lymphocytes to undergo proliferation. Excessive level of BAFF causes abnormally high antibody production and can trigger lupus. Inhibiting this pathway has led to the development of Belimumab, an anti-BLyS monoclonal antibody, which is the first to be licenced for use in lupus.

CD20 is a protein expressed on B cells. Targeting CD20 leads to a reduction in number of circulating B cells. Rituximab is a monoclonal antibody targeting CD20. Originally it was used to treat lymphoma but is now used to treat a number of B cell medicated autoimmune diseases, including lupus.

Interferon-α is a cytokine which correlates with lupus disease activity and severity. Several genes involved in the type 1 IFN pathway are associated with lupus. This has led to clinical trials with IFN-α as the therapeutic target. Although IFN-α neutralizing monoclonal antibodies (mabs) have not proved effective, there is more hope for a mab targeting the type I interferon receptor (IFNAR1). Plasmacytoid dendritic cells (pDCs) are the most potent source of IFN-α and they accumulate in inflamed target tissues in lupus patients. Biologics targeting plasma-cytoid dendritic cells are, therefore, undergoing trials. The main stimuli for the production of type I IFN are viral or cell-derived nucleic acids (DNA or RNA) that bind to intra-cellular receptors and trigger signalling pathway activation; there are, therefore, numerous clinical trials being undertaken of inhibitors of these receptors and signalling molecules.

Possibly of relevance to the type I IFN signature in lupus is the increasing evidence for viral associations with the condition - particularly Epstein-Barr virus (EBV). This is virtually ubiquitous in the adult population and, as a herpes virus, is carried for life once infection has occurred. It can, occasionally, reactivate from its latent state and, thus, the possibility exists that EBV could play a role in both the development of lupus and relapses in the established disease.

Pre-clinical studies have identified possible therapeutic targets in the autoimmune pathway such as RhoB and the complement cascade which may inform future drug development.

In addition to developing novel therapeutic agents in these areas, which is extremely costly and time-consuming, repurposing of established approved drugs is also an area of active research.

Treatment regimes

As discussed above, in the past decade there have been some exciting developments in the treatment of lupus. As well as increased knowledge about the optimal use of conventional drugs for lupus (hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, ciclosporin and corticosteroids), two new biologic drugs are now available for use.

In 2011, belimumab was approved by the US Food and Drug Administration (FDA) for use in lupus. This was the first treatment approved specifically for lupus in 50 years. NICE approved its use in the UK in 2016 as an add-on treatment for adults with active autoantibody-positive lupus where there is both serological and clinical evidence for disease activity (defined as positive anti-double-stranded DNA and low complement and a Safety of Estrogens in Lupus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score of greater than or equal to 10 despite standard treatment).

Rituximab can now also be used in the UK for people with active lupus who have failed to respond to at least 2 standard immunosuppressive therapies in combination with corticosteroids.

Patient registries such as the BILAG Biologics Register have been instrumental in monitoring use and safety of these new drugs and biosimilars going forward.

Given that it is known that corticosteroids contribute towards some of the morbidity in lupus and with the advent of these new biologic drugs there is research ongoing into whether steroid free treatment regimens are possible for people with lupus.

Other drugs in the research pipeline at present include Blisibimod, a potent and selective inhibitor of B cell activating factor (BLyS), and Atacicept, a fusion protein that blocks not only BLyS but also the proliferation-inducing ligand (APRIL), another B-cell activating factor. Current research is also focusing on using biosimilars and using approved drugs in combination.

There have been some difficulties with drugs which have shown real promise in clinical practice not meeting their primary endpoints in clinical trials. Reasons suggested for this have been down to study design, including prednisolone doses used, and the fact that lupus is a difficult disease to study due to its heterogeneity. It is hoped that lessons can be learnt in designing future studies to enable the best chance of success going forward.

Early diagnosis

There is ongoing research into the earlier diagnosis of lupus. It has been found that people with more organ damage at lupus diagnosis have a higher rate of damage accrual and mortality. Therefore, if lupus could be diagnosed earlier in the disease process, it is likely to reduce long-term organ damage and improve long-term health.

We now know that people in the UK with lupus see their GP more than twice as often as people without lupus in the 5 years prior to diagnosis. They are consulting with symptoms associated with lupus such as arthritis, fatigue, rash, and alopecia, suggesting that it may be possible to diagnose earlier if there is clinical suspicion. However, these symptoms in isolation are common and lupus is rare which meant that a computerised prediction model that had been developed was not both sensitive and specific enough to be efficient at screening for lupus in general practice.

There is ongoing research into developing multiplex tests for autoantibodies that would allow many potential biomarkers to be assessed on a tiny volume of blood e.g. a finger prick, which may facilitate point of care diagnostics. Ongoing research is looking at patent factors in delay to diagnosis, but also about patient experience and patient reported outcomes throughout the disease process to improve lifelong care.

The Future

Research into the pathogenesis and treatment of lupus is ongoing. Pre-clinical studies have identified possible therapeutic targets in the autoimmune pathway which may inform future drug development.

With advances in genetics and metabolomics we may in future be able to predict who will respond to which treatment to allow individualised therapy. It may even be possible to halt disease progression if treatment is started early enough in the disease process.

LUPUS UK continues to support an exciting program of research which will increase our growing knowledge into this complex condition.
Dr Frances Rees
Consultant Rheumatologist
Nottingham University Hospitals NHS Trust
Nottingham NG7 2UH

Dr Ian Todd
Associate Professor & Reader in Cellular Immunopathology
University of Nottingham
Nottingham NG7 2RD
Dr Peter C Lanyon
Consultant Rheumatologist