When mice that exhibit SLE-like symptoms are subjected to sleep deprivation stress, their neurons exhibit abnormal growth (left). When IL12 and 23 are blocked, the abnormal growth is reversed (right; Nobuya Abe, et al. Annals of the Rheumatic Diseases. July 11, 2022). CREDIT Nobuya Abe, et al. Annals of the Rheumatic Diseases. July 11, 2022

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects all the organ systems of the body. This chronic disease includes periods of illness, called flare ups, and periods of remission, when symptoms are few. There is so far no cure for this disease; treatments involve preventing flare ups and reducing their severity and duration. One of the most severe forms of SLE is neuropsychiatric systemic lupus erythromatosus (NPSLE), which affects the central nervous system—the brain and spinal cord.

A team of researchers, led by Professor Masaaki Murakami at the Institute for Genetic Medicine, Hokkaido University, have identified a stress-induced molecular mechanism that affects NPSLE, revealing a potential target for the treatment of the disease. Their findings were published in the journal Annals of the Rheumatic Diseases.

The research team focused on a specific type of NPSLE called Neuropsychiatric lupus with diffuse neuropsychological manifestations (dNPSLE). There are believed to be many causes for dNPSLE, but its pathogenesis remains poorly understood. The researchers were most interested in the effects of stress, as chronic stress is known to be involved in the development of many autoimmune diseases.

Brains of patients with dNPSLE show atrophy of the medial prefrontal cortex (mPFC, in red) compared to the reference brain of healthy individuals (Nobuya Abe, et al. Annals of the Rheumatic Diseases. July 11, 2022). CREDIT Nobuya Abe, et al. Annals of the Rheumatic Diseases. July 11, 2022

In order to identify stress-induced molecular mechanisms that might affect dNPSLE, they conducted experiments on mice models that exhibit SLE-like symptoms. After subjecting a set of these mice to sleep deprivation stress, they were able to identify that the medial prefrontal cortex (mPFC) of the brain was abnormally activated.

In the mPFC, the expression of at least 509 genes was significantly affected by sleep deprivation. The team specifically noted the upregulation of a microglial proinflammatory gene that is required for two interleukins, IL12 and IL23. Further, they showed that upregulation of 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 levels of IL12 and IL23 in the cerebrospinal fluid of human patients with dNPSLE were higher than that of healthy individuals, to such an extent that it can be used as a diagnostic marker. They also showed that the mPFC in dNPSLE patients is atrophied. Together, these indicate that the findings from the mice models may be applicable to humans.

“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,” said Masaaki Murakami.

A new paper in Rheumatology, published by Oxford University Press, indicates that researchers have developed a new, easier, and more accurate tool to measure the progress of lupus in patients.

Systemic lupus erythematosus affects up to 1.5 million people in the United States and about one in 1000 people in the United Kingdom. The autoimmune disease causes the body’s immune system to attack its own healthy tissues, especially the joints, skin, and kidneys. Doctors need to measure the progress of the disease to make accurate decisions about treatment. Numerous studies have shown that keeping disease activity well controlled leads to less long-term organ damage. However, in a disease with so many different features this can be difficult to assess.

The standard tool used to measure disease progression, called the BILAG-2004 index, uses multiple reference documents including a case report form, a detailed glossary, and separate scoring algorithms covering nine different areas. This is often too difficult or time-consuming for doctors to complete during routine clinic visits,  particularly for those less familiar with the format. The challenges of the standard index can make it difficult for physicians to measure disease accurately and consistently. In clinical trials, the training required is long, mistakes in scoring are common, and physicians often express frustration with the method.

Researchers developed a new “Easy-BILAG” project to help doctors assess lupus using a simpler, faster tool. Easy-BILA, is a single-page document using color-coding to make assessment more user friendly way. The researchers found that, when compared across a variety of factors, the new tool enabled more accurate, consistent, and time efficient  measurements of lupus disease progression. Overall accuracy was boosted to 96% and general hospital rheumatologists could measure disease progression accurately in 91.3% of cases using the new tool, compared with only 75% when using the more difficult standard format. Rheumatologists were able to use the new tool to assess cases faster, in under an hour. The standard format took an average 80 minutes to complete.

Rheumatologists rated the new tool as intuitive and well adapted for routine clinical practice and expressed willingness to use it routinely. “The standard-format BILAG is useful for assessing individual patients,” said the paper’s author, Edward Vital, “but its downside was always the time and training needed to complete it. Being able to measure the progress of lupus quickly and easily has transformed my practice so I’m excited that we can now make it easy for anyone to do the same.”

Dr Konstantinos Tselios presented work on the impact of time to remission and flares on the development of advanced CKD in LN. Using data from the Toronto Lupus Clinic database, the group showed that 15.8% developed advanced CKD after 9.5 years. At baseline, these patients had a higher SLICC/Damage Index, lower estimated glomerular filtration rate, higher prevalence of hypertension, proliferative nephritis, and were more often treated with ACE inhibitors or angiotensin receptor blockers.

Importantly, complete remission within the first year from LN diagnosis strongly protected against advanced CKD. However, experiencing just one flare was associated with 2.7-fold increased risk for advanced CKD. Longer time on immunosuppressives after remission was associated with decreased risk for advanced CKD. These findings emphasize the importance of early remission as well as flare prevention with prolonged immunosuppressive to maximize renal survival in LN.

Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST. The optimal duration of maintenance IST for proliferative LN is unknown. Professor Dr Noemie Jourde-Chiche shared results of the WIN-Lupus trial, which tested whether maintenance IST discontinuation after 2–3 years in patients in remission after a proliferative LN is non-inferior to IST continuation for 2 more years.

In the per-protocol population, a relapse occurred in 10.4% with IST continuation, and 25% with IST discontinuation. Non-inferiority was not demonstrated for relapse rate. Time to renal relapse did not differ between groups, and severe SLE flares (renal or extra-renal) were less frequent in patients with IST continuation compared to discontinuation, but adverse events did not differ between groups.

An abstract on integrated multilevel omics analysis revealed a set of enriched pathways of potential interest for future drug investigation in LN, with implications for proteasome inhibition. Dr Ioannis Parodis and colleagues analysed differentially expressed genes (DEGs), pathways and their druggability via the Drug Gene Interaction database (DGIdb) in 41 patients with active LN versus healthy controls. In total, 6,869 significant and validated DEGs were identified in active LN. These genes could be targeted by 203 different drugs, with the proteasome inhibitor bortezomib interfering with cathepsin B (CTSB) regulation and cyclophosphamide interfering with the regulation of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) being of particular interest.

In 2020 EULAR – the European Alliance of Associations for Rheumatology – and the European Renal Association (ERA) published updated treatment recommendations for LN. The outline targeted reductions in proteinuria over the course of the first year of therapeutic intervention. Dr Hans-Joachim Anders reported on a post-hoc analysis of pooled voclosporin data from the AURA-LV and AURORA-1 studies based on these updated response criteria.

The novel calcineurin inhibitor voclosporin was approved in 2021 in the USA for the treatment of adult patients with active LN in combination with background immunotherapy. Within the first 3 months of treatment, 78.4% of patients on voclosporin and 62.4% in the control group achieved ≥25% reduction in urine protein creatinine ratio (UPCR). After 12 months, 52.6% and 33.1% of those receiving voclosporin and control, respectively, had achieved UPCR ≤0.7 mg/mg.

The results suggest that addition of voclosporin to a background regimen of mycophenolate mofetil and low-dose steroids in patients with LN significantly increased the likelihood of achieving the UPCR targets of therapy recommended by EULAR/ERA.

In patients with lupus, immune cells undergo an inflammatory transformation when migrating from the blood to the skin.

A graphic depicting a person with lupus. CREDIT Justine Ross, Michigan Medicine.

People with lupus have overactive immune systems that attack their own tissue, causing inflammation throughout the body.

Around 70-80% of them will develop skin disease as part of their condition. And while it’s thought that exposure to ultraviolet light triggers the rashes, scientists are not sure how it ties together with the systemic inflammation.  

A Michigan Medicine study now brings more clarity, as researchers found that the normal-appearing skin of lupus patients contains the same inflammatory signals that are detected when the skin develops a rash – sometimes at even higher levels. The results are published in Science Translational Medicine.

“This really starts to piece the puzzle together of how inflammation seen in lupus patients may be related to skin exposures such as UV light,” said J. Michelle Kahlenberg, M.D., Ph.D., senior author of the study and rheumatologist at University of Michigan Health. “We were able to see the properties of normal-appearing skin in unparalleled resolution, suggesting that the skin is primed for inflammatory reactions.”

The team of researchers used single-cell RNA-sequencing analysis to assess the biopsies of both normal-appearing skin and skin from rashes of seven lupus patients. The results reveal that elevated signals of interferon, a protein known to contribute to UV sensitivity, were robustly present in all lupus biopsies compared to healthy control skin – with the strongest signal coming from the healthy-appearing skin, not the inflamed skin.

These interferon-rich inflammatory properties weren’t just found in the keratinocytes, the cells that make up the epidermis of the skin. Researchers saw the same inflammatory changes in the fibroblasts that generate the connective tissue of the skin.

“This is really important because we have a new drug that can block interferon signaling in lupus, and people are trying to figure out how best to use that medication,” said Kahlenberg, who is also an associate professor of rheumatology at U-M Medical School. “So, validating this abnormality in the interferon pathway could be essential for determining the best course of treatment for scores of lupus patients.”

Cell education

The researchers also took blood samples of the same patients to examine how immune cells are promoting skin inflammation in lupus. Their data suggest that a subtype of monocytes, important members of the innate immune system, are exiting the blood into the skin of lupus patients. Upon moving into the skin, they undergo a striking inflammatory transformation.

Kahlenberg calls it “cell education.” The lupus skin environment itself – specifically, the interferon within the skin – appears to change the monocytes in a way that sets up the rest of the immune system to be turned on.

Interferon plays a critical role in the innate immune system. It alerts the cells to dangerous invaders such as viruses. In many autoimmune diseases, however, interferon is overproduced in the absence of any real threat, changing how immune cells behave.

“These interferon-educated immune cells seem to be priming many different cell types in the skin to overreact to stimuli with excessive inflammatory responses, manifesting as disfiguring skin lesions,” said Allison C. Billi, M.D., Ph.D., co-first author of the study, dermatologist at U-M Health and assistant professor of dermatology at U-M Medical School. “We don’t yet know all of the stimuli that can tip the balance and precipitate these rashes, but UV light certainly appears to be one of them.”

Previous research analyzing the blood of lupus patients has struggled to identify potential biomarkers for disease flares. Knowing that the monocytes became more inflammatory when traveling to the skin, Kahlenberg believes the same process could also trigger systemic immune flares in other organs affected by lupus, such as the kidney and brain.

“In future studies, we will want to look at these target organs to really understand what’s going on,” she said. “These cells transformed so robustly when they migrated into the skin it suggests that if we look for biomarkers only in the blood, we will likely miss what is really happening in the organs.”

Billi says understanding changes at a cellular level will enable precision medicine in lupus patients, which would employ individualized analysis to guide medical decisions and treatment options.

“Research has been hampered by how differently lupus presents across individuals,” she said. “By focusing on patients with lupus affecting a single organ – the skin – we have gained some insight into which cells are orchestrating lupus inflammation and how.”