A recent phase 2 clinical trial published in Arthritis & Rheumatologyhas reported promising results for deucravacitinib, an oral inhibitor tyrosine kinase 2 (TYK2) inhibitor, in patients with active lupus.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by the presence of antinuclear autoantibodies and diverse clinical manifestations. Treatment often lacks efficacy for SLE patients, and current therapies are associated with undesirable side effects.
TYK2 is an intracellular kinase that mediates signalling of key cytokines involved in the pathogenesis of SLE. A biologic agent targeting the type I interferon (IFN) receptor has been approved in SLE. Deucravacitinib is an oral, selective, allosteric inhibitor of TYK2 that binds the regulatory domain and locks the enzyme in an inactive state distinguishing it from JAK inhibitors that bind the highly conserved active domain
For the trial, adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomised 1:1:1:1 to receive deucravacitinib 3mg twice daily, 6mg twice daily, 12mg once daily, or placebo. The primary endpoint was SRI-4 and secondary outcomes were assessed on a variety of disease activity measures.
At week 32, the percentage of patients experiencing benefits was 34% with placebo compared with 58%, 50%, and 45% with the respective deucravacitinib regimens.
Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported.
The autoimmune disease lupus has no cure, and current treatment is limited in its effectiveness in reducing symptoms and controlling damage to the body. Now, scientists report they have begun phase 2 clinical trials with 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.
“Few new therapies have succeeded, but we believe our compound could be an effective treatment for lupus,” says Alaric Dyckman, PhD. 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.
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.
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,” explained Dr 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 an interferon receptor, while GlaxoSmithKline’s belimumab reduces the survival of 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, Dr Dyckman noted, while steroids and general immune suppressants are associated with safety concerns and were not originally designed to treat lupus.
The BMS researchers started by screening the company’s compound collection for molecules that could block TLR7/8 signalling. The team refined the search further to improve interaction with other receptors, and potency, and enablee 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,” Dr Dyckman said. “We hadn’t seen that reversal with other mechanisms we had evaluated, so we were particularly excited about that finding.” Dr Dyckman said that he believes afimetoran effects together may let it control lupus as well as or better than existing treatments, doing it through an oral route.
Afimetoran also combined well with corticosteroid treatments in mice, so patients might be able to use lower doses of steroids and reducing associated side effects.
Phase 1 clinical trials of afimetoran have been completed. The trials showed that a low, once-daily oral dose was safe in healthy patients and could almost completely block signalling through TLR7/8. And now, a phase 2 trial to test its effectiveness in lupus patients is underway. Because of its mode of action, Dr Dyckman said, 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.
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,” Dr Dyckman said. “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.”
A team of researchers have identified a molecular mechanism by which stress affects a neuropsychiatric form of lupus, revealing a potential target for the treatment of the disease. Their findings were published in Annals of the Rheumatic Diseases.
Neuropsychiatric systemic lupus erythromatosus (NPSLE), which affects the central nervous system is one of the most severe forms of lupus, for which there is currently no cure. NPSLE is the least understood yet maybe the most prevalent manifestation of lupus, comprising 14%–80% or more of adult SLE cases and 22%–95% of paediatric cases. It can occur independently of active systemic disease and without serologic activity and is associated with increased morbidity and mortality
The research team, led by Professor Masaaki Murakami at Hokkaido University, focused on a specific type of NPSLE called Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE). There are believed to be a number of causes for dNPSLE, but little is known about its pathogenesis. The researchers were primarily interested in the effects of stress, as chronic stress is linked to the development of many autoimmune diseases.
The researchers conducted experiments on mice models that exhibit SLE-like symptoms to identify the underlying mechanisms dNPSLE. After subjecting a set of these mice to sleep deprivation stress, they observed that the medial prefrontal cortex (mPFC) of the brain was abnormally activated.
In the mPFC, at least 509 genes’ expressions were significantly affected by sleep deprivation. In particular, there was an upregulation of gene that is required for two interleukins, IL12 and IL23. They further showed that upregulating these two interleukins caused activation of the microglial cells of the mPFC. Blocking IL12 and IL23 pathways in these sleep-deprived mice models inhibited the stress-induced neuropsychiatric symptoms.
Most importantly, they showed that there were elevated levels of IL12 and IL23 in the cerebrospinal fluid of human patients with dNPSLE, which could constitute a diagnostic marker. They also showed that the mPFC in dNPSLE patients is atrophied; together, these observations indicate that the mouse model findings may be applicable to humans.
Summing up, Prof Murakami said: “In revealing the effect of the stress-induced effects on the expression of IL12 and IL23 in dNPSLE, we have identified them as not only a diagnostic marker but also a novel therapeutic target for this disease.”
While a large, long-running epidemiologic study was unable to conclude that ultraviolet (UV) radiation in sunlight can cause new-onset systemic lupus erythematosus (SLE), trends in the data suggested that it could, according to findings reported in the journal Arthritis Care & Research.
Participants in the who were in the upper tertile (third) of estimated UV-B exposure had 28% higher rates of incident SLE during follow-up.
Similar numerical increases in risk with high estimated UV-B exposure were seen for specific lupus subtypes and manifestations, such as SLE with photosensitivity or with anti-Ro/La antibodies, which also fell short of statistical significance, they reported
The study’s relatively small number of new-onset SLE cases – only 297 out of about six million person-years of data – was the likely reason for the broad confidence intervals. The study did also find one lupus subtype with a statistically significant association with UV-B exposure: SLE with malar rash (HR 1.62 for top versus bottom tertile, 95% CI 1.04-2.52).
“We found no overall association between high UV radiation exposure and risk of overall SLE in these large cohorts of women prospectively followed for many years prior to SLE onset,” the researchers acknowledged.
“However, cumulative average UV radiation exposure in the highest tertile was associated with non-significant but suggestive increased risk of the subtype of SLE presenting with cutaneous antibodies, including anti-Ro and/or anti-La antibodies, and/or cutaneous involvement, including malar rash (acute cutaneous lupus) and/or photosensitivity, which tend to co-occur, and are biologically plausible,” they stated.
Photosensitivity is a hallmark of lupus, and sunlight exposure is known to cause disease flareups in people with established SLE. Among the 297 cases of incident SLE that developed in NHS participants, 58% included photosensitivity. Other risk factors include smoking and exposure to silica. Exposure to strong sunlight might be another one, since UV radiation disrupts skin keratinocytes, releasing antigens that could trigger autoimmune attack.
The decades-long American Nurses’ Health Study (NHS) I and II has the medical records of 240 000 participants, mostly female, who completed detailed questionnaires.
However, new-onset SLE is rare enough that, even with that many participants, there weren’t enough cases to be sure whether risk increases in the 30%-50% range were real.
Other major limitations included having to estimate UV exposure from participants’ residence, race serving as an inexact proxy of skin tone, and no data on sunburn history or sunscreen use.
Facial rash characteristic of lupus. Credit: Statpearls
A study published in Nature has identified mutations in an X chromosome gene that senses viral RNA, as a cause of the autoimmune disease lupus, a finding which may explain why the disease is far more common in females, and which might lead to new treatments.
In the study, whole genome sequencing was performed on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus at age 7. Such a severe case with early onset of symptoms is rare and suggests a single genetic cause.
In their genetic analysis, the researchers discovered a single point mutation in the TLR7 gene. Referrals from other institutions, they were able to identify other cases of severe lupus where this gene was also mutated.
To confirm that the mutation causes lupus, the team inserted the gene into mice, which went on to develop the disease and showed similar symptoms. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery.
Carola Vinuesa, senior author and principal investigator said: “It has been a huge challenge to find effective treatments for lupus, and the immune-suppressors currently being used can have serious side effects and leave patients more susceptible to infection. There has only been a single new treatment approved by the FDA in about the last 60 years.
“This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise.”
Professor Nan Shen, co-director of CACPI adds: “While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”
The mutation identified by the researchers makes TLR7 protein bind more readily guanosine and become more active. This in turn increases the sensitivity of the immune cell, making it more likely to incorrectly target healthy tissue.
Interestingly, other studies have shown mutations that cause TLR7 to become less active are associated with some cases of severe COVID infection, highlighting the delicate balance of a healthy immune system.
The findings could also explain why lupus is 10 times more common in females than in males. Because TLR7 is located on the X chromosome, females have two copies of the gene while males have one. Usually, in females one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. This means females with a mutation in this gene can have two functioning copies.
Study co-author Dr Carmen de Lucas Collantes, said: “Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery.”
Gabriela, now a teenager, remains in touch with the research team. She said, “I hope this finding will give hope to people with lupus and make them feel they are not alone in fighting this battle. Hopefully the research can continue and end up in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”
The researchers are now investigating the repurposing of existing treatments which target the TLR7 gene. By targeting this gene, they hope to be able to also help patients with related conditions.
Carola added: “There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus. TLR7 may also play a role in these conditions.”
A new study revealed that lupus may be triggered by a defective process in the development of red blood cells (RBCs) which leaves mitochondria remnants. The study was published in Cell.
The researchers found that in a number of lupus patients, maturing red blood cells fail to get rid of their mitochondria, which are normally excluded from red blood cells. This abnormal retention of mitochondria can trigger the cascade of immune hyperactivity characteristic of this disease.
“Our findings support that red blood cells can play a really important role in driving inflammation in a subgroup of lupus patients. So this adds a new piece to the lupus puzzle, and could now open the door to new possibilities for therapeutic interventions,” said the study’s senior author, Dr Virginia Pascual, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine
Lupus is a chronic disorder with no cure that features intermittent and sometimes debilitating attacks by the immune system on the body’s own healthy tissues, including skin, joints, hair follicles, heart and kidneys. A common underlying factor in lupus is the abnormally elevated production of immune-activating proteins called type I interferons. Treatments aim to suppress immune activity, including interferon-driven inflammation.
Previous research found defective mitochondria in the immune cells of lupus patients. In the current study, the researchers focussed on red blood cells, which should lack mitochondria. Many lupus patients had red blood cells with detectable levels of mitochondria, and more common in patients with worse symptoms. By contrast, healthy controls had no mitochondria-containing red blood cells.
Lead author of the study, Dr. Simone Caielli, assistant professor of immunology research at the Drukier Institute and the Department of Pediatrics at Weill Cornell Medicine, then studied how human red blood cells normally get rid of mitochondria as they mature, as prior studies had mainly examined this in mice, and why this process could be defective in lupus patients.
Subsequent experiments showed these abnormal red blood cells cause inflammation. Normally, when red blood cells age or display signs of damage they are removed by macrophages, with binding antibodies helping removal. When the macrophages ingest them, the mitochondrial DNA in the red blood cells triggers a powerful inflammatory pathway called the cGAS/STING pathway, in turn driving type I interferon production. These findings show that “those lupus patients with mitochondria-containing red blood cells and evidence of circulating anti-RBC antibodies had higher interferon signatures compared to those who didn’t,” Dr Caielli said.
The researchers are now investigating how the mitochondria is retained in these cells. Identifying lupus patients with these cells could help predict when they are likely to undergo lupus flares and to develop therapies.
AstraZeneca announced that its type 1 interferon receptor antagonist anifrolumab (Saphnelo) has received approval from the US Food and Drug Administration for the treatment of moderate-to-severe systemic lupus erythematosus alongside standard therapy.
“This is wonderful, exciting news, and is great for the lupus community — patients, family members, and clinicians who treat patients,” said Richard Furie, MD, chief of rheumatology at Northwell Health in Great Neck, New York, in an interview.
Only belimumab (Benlysta) in 2011 and voclosporin (Lupkynis) for lupus nephritis a few months ago had been approved in the past decades. “And that represents 25 years of trying,” Dr Furie said.
Significant benefits were reported in 2016 in a phase IIb trial known as MUSE. In that trial, 62.6% of patients receiving 300 mg intravenous anifrolumab every 4 weeks had an SLE Responder Index score of 4 (SRI-4) plus a reduction in the steroid dose to less than 10 mg/day compared with only 17.6% of patients in the placebo group, which was a significant difference — the best lupus trial data so far, according to Dr Furie.
Two pivotal phase III trials, TULIP-1 and TULIP-2, followed, with conflicting results.
In TULIP-1, the primary endpoint of Systemic Lupus Erythematosus Responder Index (SRI-4) was not met. After a year, an SRI-4 response was seen in 36% of patients receiving anifrolumab and in 40% on placebo. Some secondary endpoints suggested benefits, including the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA).
In TULIP-2, patients were randomised 300 mg intravenous anifrolumab or placebo every 4 weeks for 48 weeks, with a BICLA response as the primary endpoint. After a year, 47.8% of patients in the anifrolumab group achieved a BICLA response compared with 31.5% of placebo patients.
“We were all shocked when TULIP-1 failed,” said Dr Furie, who is also a leading member of the Lupus Research Alliance’s Lupus Clinical Investigators Network. “But it didn’t really fail — it depends on how you define failure. It did not reach the primary endpoint, but on the other composite, BICLA, it was successful, as well as on a lot of the key secondary endpoints. The totality of the data, I think, is the key phrase,” he said.
“I think the two studies were more similar than dissimilar. You have to have an appreciation of how difficult it is doing clinical trials in lupus. For every one trial that has been successful, there have probably been 10 that were unsuccessful,” he said.
This was not the first time discordant results had been seen in lupus trials. “We also saw discordance between the BICLA and SRI in the ustekinumab phase II trial,” he noted.
