Lupus is an autoimmune disease that attacks organs and can be fatal. There’s no cure, so current treatments aim to limit damage and ameliorate symptoms. Some of these therapies have to be injected, some have serious side effects, and many aren’t very effective. But today, scientists report they have begun phase 2 clinical trials with a pill containing a compound that, in mice, not only prevents lupus-like symptoms, but also reverses signs of organ damage caused by the disease and prevents death.

The researchers will present their results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2022 is a hybrid meeting being held virtually and in-person Aug. 21–25, with on-demand access available Aug. 26–Sept. 9. The meeting features nearly 11,000 presentations on a wide range of science topics.

“Few new therapies have succeeded, but we believe our compound could be an effective treatment for lupus,” says Alaric Dyckman, Ph.D. The disease affects 5 million people worldwide, according to the Lupus Foundation of America. Symptoms include rashes, extreme fatigue, pain, inflammation and deterioration of organs, such as the kidneys and heart, which can lead to death.

Lupus develops when the immune system attacks the body’s tissues. Years ago, researchers began suspecting that this process involved toll-like receptors (TLRs) 7 and 8, which are cellular proteins that activate the immune system when they detect viral RNA or mistakenly identify a person’s own RNA as a threat.

“Genetic data and evaluations of injectable treatments suggested TLR7 and 8 could be drug targets for lupus. What was missing was an ability to directly block these receptors with small molecules that could be taken orally,” says Dyckman. So in 2010, he and other scientists at Bristol Myers Squibb (BMS) set out to develop such compounds.

New options would be welcome, since many patients don’t respond fully to current medications. The two approved therapies that were specifically developed for lupus reduce activity of specific immune system components: AstraZeneca’s anifrolumab blocks a receptor for the protein interferon, while GlaxoSmithKline’s belimumab reduces the survival of white blood cells known as B cells. Other treatments include steroids and other general immune suppressants, anti-malarials, anti-inflammatories and anticoagulants. However, anifrolumab and belimumab must be given by injection or infusion, Dyckman notes, while steroids and general immune suppressants are associated with safety concerns and were not originally designed to treat lupus.

The BMS researchers began zeroing in on a suitable alternative by screening the company’s compound collection for molecules that could block TLR7/8 signaling. The team modified the structures of the initial hits to reduce interaction with other receptors, improve potency and enable oral dosing. The resulting compound, “afimetoran,” binds to the target TLRs, inhibiting their operation to achieve beneficial activity. Like anifrolumab, it interferes with interferon, and like belimumab, it controls damage from overactive B cells. It also inhibits the production of multiple proinflammatory cytokines that cause a lot of tissue damage in lupus.

“With afimetoran, not only could we prevent the development of lupus-like symptoms in mice before their disease onset, but we could actually reverse the symptoms and prevent death in animals that were days or weeks away from succumbing to the disease,” Dyckman says. “We hadn’t seen that reversal with other mechanisms we had evaluated, so we were particularly excited about that finding.” Dyckman says he believes the combined effects of afimetoran give it the potential to control lupus as well as or better than existing treatments and do so through an oral delivery, as opposed to requiring injection or infusion.

The team also found that afimetoran combined well with corticosteroid treatments in mice. That means patients might be able to use lower doses of steroids, a mainstay of lupus treatment. Lower doses would be beneficial because steroids have side effects, such as weight gain, thinning bones, high blood pressure and diabetes, as well as an increased risk of infection.

Phase 1 clinical trials of afimetoran to evaluate safety in healthy people and shed light on the compound’s behavior in the body have been completed. The trials showed that a low, once-daily oral dose could almost completely block signaling through TLR7/8. And now, a phase 2 trial to test its effectiveness in lupus patients is underway. Because of its mode of action, Dyckman says, it may also work in other autoimmune disorders, such as psoriasis or arthritis.

BMS is testing other compounds against lupus, such as deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor that is moving into phase 3 studies. Other companies are also making progress. Merck, for instance, is evaluating its own oral TLR7/8 blocker, enpatoran, in phase 2 trials.

But the crowded field doesn’t concern Dyckman. Despite intensive efforts to develop new therapies over the past several decades, few have succeeded. “So getting a lot of shots on goal is important,” he says. “Also, lupus is such a heterogeneous disease that it’s unlikely that any single approach will provide relief for all of the patients out there.”

Researchers at Michigan Medicine have uncovered the molecular mechanism that drives the disease-causing effects of the most common genetic risk factor for lupus, a study suggests.

Systemic lupus erythematosus is a common, incurable autoimmune disease that affects millions of individuals worldwide, with a particularly high prevalence among women. A genetic variant, called HLA-DRB1*03:01, is the greatest risk factor for the condition, which involves inflammation in many vital organs, and can lead to severe disability and death.

In a study recently published in Communications biology (a Nature Portfolio journal), investigators found that a protein coded by that HLA variant triggers a cascade of molecular and cellular effects that can cause the inflammatory symptoms seen in lupus patients.

“For the first time, we have found the enigmatic mechanism that genetically predisposes people to the worst effects of the most typical form of lupus,” said Joseph Holoshitz, M.D., senior author of the paper and professor of internal medicine and rheumatology at University of Michigan Medical School. “The findings could potentially facilitate the discovery of safe, simple and effective treatments for SLE by targeting this new pathway.”

The results support a novel theory how genetic variants of the kind of HLA-DRB1*03:01 can lead to autoimmune diseases independent of antigen presentation, the traditionally studied mechanism, which has been long proposed but, so far, not directly proven.

“We have identified a chain of events in cell culture, as well as a mouse model of the disease, that demonstrate how the abnormalities that can cause lupus develop from the first effect of the risk gene, to signaling, all the way to immune abnormalities and clinical manifestations of lupus,” said Bruna Miglioranza Scavuzzi, Ph.D., first author of the paper and a postdoctoral research fellow in the Division of Rheumatology at the University of Michigan Medical School.

The findings of this study are reminiscent of previous findings in rheumatoid arthritis, another HLA-associated disease, that have paved the way for the development of small molecules to effectively treat arthritis in mice, Holoshitz says.

“Human trials in RA with those compounds are being carried out, and I hope that our novel findings will lead to similar efforts to ease the burden of millions of lupus patients as well.” he said.

 A National Jewish Health led study recently published in Lupus finds that technology through video game-based cognitive therapy improves attention and executive functioning in patients with systemic lupus erythematosus (SLE).

There are treatments to improve the physical symptoms that people with lupus suffer from, such as muscle pain, joint pain, fatigue, rashes and swelling.    “Patients with lupus may also experience a variety of cognitive problems,” said lead author of the study Elizabeth Kozora, Ph.D., a research and clinical neuropsychologist at National Jewish Health.  “There are few treatment options available to improve cognitive deficits in SLE, which is what makes this innovative study utilizing non-invasive technology exciting.”

In the study, patients with SLE first completed baseline neuropsychological tests of attention and psychomotor speed and flexibility using standardized paper and pencil tests, as well as a novel tablet-based digital platform.  The patients were randomized into treatment and control groups and returned four weeks later for follow-up testing for cognitive and behavioral testing.  Patients in the treatment group completed five sessions of a video game intervention, five times a week for four weeks.  The video game-like treatment group had significant improvement in visuomotor speed and complex attentional sequencing skills compared to the control group; a finding consistent with other studies utilizing this treatment in patients with attention deficit hyperactivity disorder and depression.  “We believe that SLE patients would benefit from participation in digital interventions designed to interact with the prefrontal networks of the brain,” said Dr. Kozora.  

In the adult neuropsychology clinic at National Jewish Health, a number of autoimmune patients, including those with lupus, will likely benefit from having expanded treatment options for cognitive difficulties that researchers are working to develop.

People with systemic lupus erythematosus, or SLE, who received a “booster” dose of SARS-CoV-2 vaccine after full vaccination are roughly half as likely to have a subsequent “breakthrough” COVID-19 infection, a new study shows.

The finding, researchers say, should offer reassurance to the more than 200,000 Americans who have SLE, a condition in which the body’s immune system mistakenly attacks its own healthy tissues, especially joints and skin. Immune-suppressing drugs, such as steroids, needed to control symptoms of the disease, place them at increased risk of infections, including SARS-CoV-2.

Led by researchers at NYU Grossman School of Medicine, the new study tracked the health of 163 fully vaccinated men and women being treated for SLE at its affiliated hospitals in New York City. The researchers’ goal was to see who became infected with the virus over at least six months, given that more than half were taking at least one immune-suppressing medication for their SLE. All had received some combination of the vaccines manufactured by Pfizer, Moderna, or Johnson & Johnson prior to June 2021, but only 125 had received a third or booster dose of vaccine.

Publishing in the journal The Lancet Rheumatology online July 12, the study showed that at the end of the monitoring period (April 24, 2022), 44 vaccinated SLE patients had had breakthrough infections, with two needing hospitalization (but both surviving their infection).

Among those with breakthrough infections, 28 of 125, or 22%, had received a booster, while 16 of 38, or 42%, had not. Notably, according to investigators, the majority of breakthrough infections (42 of 44) occurred after Dec. 2, 2021, when the city detected its first case of the highly contagious omicron variant.

Another key study finding was among 57 of the study participants who agreed to have their blood antibody levels checked, once after full vaccination and again after receiving their booster.

Researchers found that even those on immunosuppression who had not responded to the initial round of vaccination had an immediate rise in antibody levels after the administration of a booster shot. Previous research had shown that these antibody levels were lower among many initially vaccinated patients with rheumatic diseases, including SLE, who were taking immune-suppressing drugs, sparking fears of waning immunity to COVID-19 over time.

However, study results showed those with higher levels of antibodies, needed to block the SARS-Cov-2 “spike” protein and prevent the virus from infecting human cells, were no more protected from breakthrough infection than those with lower spike-protein antibody levels.

Still, researchers say their previous work showed elevated antibody levels in fully vaccinated lupus patients strengthened key measures of long-term immunity, which may help explain the lack of severe disease in those with breakthrough infections.

“Our study results offer people living with systemic lupus erythematosus clinical confirmation that vaccines are highly effective at guarding against severe COVID-19, despite their increased risk of catching the disease,” says study co-lead investigator and rheumatologist Amit Saxena, MD, MS.

“COVID-19 vaccine boosters, or third shots, offered an added, doubled layer of protection from breakthrough infection,” says Saxena, an assistant professor in the Department of Medicine at NYU Langone Health. “Even in cases of SARS-CoV-2 infection, cases were overwhelmingly mild among SLE patients who were fully vaccinated.”

“Our research also shows that most people with systemic lupus erythematosus who are fully vaccinated and boosted mounted good responses despite being on immune suppression,” says study co-senior investigator and rheumatologist Peter Izmirly, MD. Izmirly is an associate professor in the Department of Medicine at NYU Langone Health.

However, researchers caution that further monitoring of patients is needed to determine if there is any antibody “cutoff” level below which SLE patients become more vulnerable to SARS-CoV-2 infection.

During the initial wave of the pandemic in spring 2020, NYU Langone hospitalization rates for its SLE patients were more than double those of its patients without the condition, the researchers note, although death rates were the same.