Physicians, researchers and patients came together in Berlin last week for the 2012 Annual European Congress of Rheumatology (EULAR). The four-day program covers the gamut of rheumatological diseases and includes new advances in basic science, new treatments, and clinical practice. In attendance to represent the Lupus Research Institute (LRI) and report on the key lupus news from the lab and clinic was Dr. Jen Bell, LRI Research Director.
Following are summaries of key research findings with the greatest potential to make a difference for people with lupus.
Putting the Brakes on B Cells — Abstract
Early findings presented by Dr. Thomas Dörner (Charité Berlin & German Rheumatism Research Center) provide new understanding of the possible benefits of epratuzumab treatment, a potentially new monoclonal antibody therapy in lupus.
In lupus, the B cells of the immune system are abnormally active, causing them to produce antibodies that attack the skin, joints, heart, kidney and central nervous system. Epratuzumab, which is directed against a specific molecule on the surface of a B cell, CD22, is one of several new drugs being tested in lupus that aim to treat disease by specifically targeting B cells.
Epratuzumab is currently being tested in lupus patients in two Phase III clinical trials (EMBODY) sponsored by the pharmaceutical company UCB. Unlike another B-cell targeted monoclonal therapy rituximab, epratuzumab does not eliminate B cells, but precisely how the drug acts on B cells is not well understood.
Dr. Dörner and colleagues switched on human B cells in the lab, simulating what happens in lupus. They found that when epratuzumab was present, the signals that switch on the cells were partly inhibited. So epratuzumab may act as a brake, holding B cells back from making antibodies against harmless body components.
“The mechanism we have identified of inhibiting intracellular activation pathways by binding to the CD22 molecule needs to be further explored, said Dr. Dörner. “Epratuzumab has the potential to partially block these signals, but we need to see if this activity is enough to suppress disease in the ongoing clinical trials in SLE.”
See www.lupustrials.org for more information on EMBODY and other lupus clinical trials currently enrolling volunteers.
New Anti-interferon Treatment Passes First Hurdle — Abstract
AGS-009, a new monoclonal antibody-based therapy targeting interferon-alpha is safe in lupus patients and able to neutralize interferon-alpha activity, according to new clinical trial results reported at EULAR 2012.
Interferon-alpha, a chemical messenger of the immune system, is overproduced in lupus and thought to be at the crux of the disease. A number of agents that target interferon-alpha are currently being studied for use as a treatment for lupus. Results from the Phase I trial of an interferon-alpha specific monoclonal antibody being developed by Argos Therapeutics called AGS-009 found the drug safe and well tolerated. In addition, there was evidence that AGS-009 is able to neutralize its target.
Based on these positive results Argos Therapeutics hopes to begin new trials to determine if AGS-009 is effective in treating lupus.
Cancer Drug May Help Treatment-Resistant Lupus — Abstract
Bortezomib (Velcade), a drug for a type of cancer myeloma, may have promise for lupus patients who have failed to respond to conventional treatments, according to a pilot patient study presented at EULAR 2012. Bortezomib targets antibody-producing cells, which in lupus produce harmful antibodies against the body’s cells and tissue.
Previously, Dr. Reinhard Voll and colleagues at Freiburg University Medical Center in Germany showed that bortezomib is effective in treating lupus kidney disease in mice.
In the new study, 13 patients whose condition had not improved despite treatment with many conventional lupus drugs were given up to four courses of bortezomib. Eight patients showed a marked improvement in their disease. Of the remaining five patients, three had to discontinue treatment due to severe side effects and two dropped out of the study.
Bortezomib is known to have a large number of severe side effects which limit its use but, according to Dr. Voll, if the findings are confirmed in a clinical trial, the drug could be a new treatment option in lupus patients who do not respond to standard treatment with immunosuppressants.
People Newly-diagnosed with Lupus At Greatest Risk for Seizures — Abstract
Lupus patients are most likely to experience seizures within the first year after they are diagnosed with the disease, according to a new international study reported at EULAR 2012.
Many lupus patients will experience symptoms such as depression, seizures and memory problems at some time in the course of the disease. The questions researchers aimed to answer were why and how.
The 10-year prospective study of over 1600 patients in 11 countries aimed to establish how often and when seizures occur in lupus, and to find out which patients are at greatest risk.
One in 20 lupus patients who had just been diagnosed had at least one seizure. Most of their seizures (86%) were linked directly to lupus. Seizures were most likely to occur soon after diagnosis, within the first year. But there’s good news. Among those patients who experienced seizures these results showed that seizures tended to stop occuring without long-term medication. And there was no evidence that lupus seizures have a lasting impact on how patients describe their quality of life.
Lupus patients of African ancestry had a higher risk of seizures, as did patients whose disease had caused damage to organs other than the central nervous system. There was also evidence that the anti-malaria drug hydroxychloroquine may protect against seizures.
“The results of this and other studies on nervous system events in lupus patients currently being conducted by the Systemic Lupus Erythematosus Collaborating Clinics (SLICC) research network provides valuable information on the diagnosis, impact and outcome of this important aspect of SLE,” commented Dr. John Hanly, Capital Health and Dalhousie University, Canada and Chair of SLICC.
Immune system switch defective in lupus — Abstract
Cells that protect against autoimmunity are mistakenly turned off in lupus due to a faulty molecular switch, according to new research reported at EULAR 2012.
These T regulatory cells are a specialized type of T cell whose job is to control harmful autoimmune responses. Scientists already know that in patients with lupus there are fewer regulatory T cells and that they do not work properly. But the reasons have not been known.
Dr. Klaus Tenbrock (RWTH University of Aachen, Germany) previously found that T cells from lupus patients contain abnormally high levels of a protein known as CREM-alpha. New research in mice by Kim Ohl in Dr. Tenbrock’s group shows that high levels of CREM-alpha ‘turn off’ regulatory T cells by blocking a critical gene known as FoxP3. This work won Ms. Ohl one of six basic science Abstract Awards at EULAR 2012.
The researchers are now exploring whether CREM-alpha has potential as a therapeutic target to switch regulatory T cells back on in lupus.
Regulatory B cells in the Spotlight — Abstract
B cells that regulate the immune system and thereby prevent rather than promote autoimmune diseases were the focus of a EULAR 2012 session on Thursday June 7th.
In lupus, the B cells of the immune system are usually viewed as the enemy within, pumping out dangerous autoantibodies that attack the body’s own cells, damaging tissues and essential organs such as the kidney and brain. But researchers have made the unexpected discovery that B cells can also protect against autoimmune diseases.
Dr. Claudia Mauri (University College London, UK) found that healthy people have certain B cells, called regulatory B cells, that stop the immune system from attacking the body. Her recent research shows that these cells are defective in patients with lupus. But in lupus patients who respond to B-cell-depletion-therapy, such as rituximab, regulatory-B-cells are restored, suggesting these cells may contribute to the improvement in disease.”
“Our goal is to understand how regulatory-B-cells work in healthy people and why they stop working in lupus patients,” said Dr Mauri. “Being able to distinguish regulatory B cells from harmful B cells will be important for the development of new lupus therapies that target B cells and selecting the right treatment for the right patient.”
Dr. Simon Filatreau (Deutsches Rheuma-ForschungsZentrum, Berlin, Germany) and Dr. Thomas Tedder (Duke University, North Carolina, USA) each discovered similar regulatory B cells. Both presented new insight on how these cells develop and hold immune responses in check. With better understanding researchers may be able to harness regulatory B cells to treat lupus and other autoimmune diseases.
New Lupus Nephritis Guidelines Urge Early Biopsy — Abstract
European patients are set to benefit from new EULAR recommendations on the diagnosis and management of lupus affecting the kidneys. About half of people with lupus will develop kidney complications (lupus nephritis), which can lead to kidney failure in the worst cases.
Dr. George Bertsias (University of Crete, Greece) announced the new guidelines on June 7th at EULAR 2012, on behalf of the 32-member working group. "The management of lupus nephritis has been a hotly debated issue, and there is considerable uncertainty among treating physicians", Dr. Bertsias explained in EULAR News.
Among the 28 recommendations, physicians are now advised to do a renal biopsy (remove and study a tissue sample of the kidney) at the first suspicion of a kidney problem so they can diagnose quickly. The guidelines also cover which immunosuppressant drugs and doses of corticosteroids should be used, and provide specific advice for managing lupus nephritis (kidney disease resulting from lupus) in pregnant women and children.