BOSTON—As rheumatology researchers dig deeper into mechanisms of autoimmunity, they find more clues to understand how and why patients develop rheumatic diseases, triggers for life-altering symptoms and who may respond to current treatment options. Before a packed ballroom, six researchers speaking at the Plenary Session II: Discovery 2014 at the ACR/ARHP Annual Meeting in Boston on Nov. 17, 2014, offered updates on their ongoing research and newly published findings.
STING Pathway
Bone remodeling in autoimmune disease is regulated by the stimulator of interferon genes or STING pathway, said Rebecca Baum, a researcher at University of Massachusetts Medical School in Boston. Cystolic DNA sensors like STING play a role in autoimmunity, and STING mediates interferon type-1 (IFN) and interleukin 6 (IL-6) production, she said.
In mice deficient in endonucleic acid DNASEII, endogenous DNA accrual led to the production of proinflammatory cytokines, such as type 1 IFN and IL-6, Ms. Baum said. The mice developed distal polyarthritis in their limbs that resembled rheumatoid arthritis.
In further research, the ankle joints of mice deficient in DNASEII and IFNaR developed synovial inflammation and osteoclast-mediated, articular bone erosions. Unexpectedly, they also showed trabecular bone accrual, “so much so that by 16 months, the marrow space is almost entirely obliterated,” Ms. Baum said. Mice with this phenotype also showed increased osteoblast production and activity, and had enlarged spleens that contained ectopic bone fragments, she said.
To confirm STING’s role in bone formation, they bred triple-knockout mice that also had STING deficiency and found that it ameliorated arthritis and bone accrual. The triple-knockout mice had significant decreases in inflammation and decreased bone accrual in their long bones and spleens.
“We reason that because inflammation is markedly attenuated, this DNA accrual may be driving factors through the STING pathway that leads to osteoblast differentiation,” Ms. Baum said. Further, leukocyte-inhibitory factor (LIF) is induced via STING in macrophages that engulf DNA and may mediate osteoblast differentiation, she added.
Reduced Fracture Risk
Denosumab treatment, along with calcium and vitamin D supplementation, reduced cortical bone loss and reduced wrist fracture risk in older women participating in the FREEDOM trial and its extension, said Jacques P. Brown, MD, FRCPC, head of the Division of Rheumatology at the Université Laval in Quebec. Denosumab inhibits RANK ligand.
At the end of the initial, three-year trial, women taking only calcium and vitamin D showed a significant decrease in 1/3 radius bone mineral density (BMD) and were offered to enroll in a trial extension, Dr. Brown said. Two thousand two hundred and seven women, most older than 65 years old, took 60 mg of denosumab every six months. After three years of treatment, researchers found that participants’ BMD returned to baseline and then increased 1.5% after five years.
Wrist fracture rates also dropped significantly once these women added denosumab, Dr. Brown said. In the original three-year trial, the placebo group’s wrist fracture rate increased by 1.02%. After three years of the denosumab extension, the rate dropped to 0.96%, and at years four and five, it dropped to 0.58%. A subset of participants with femoral neck T-scores of ≤2.5, “a very well-known risk factor for fracture, saw an almost 80% reduction in the occurrence of wrist fracture,” Dr. Brown said.
Autotaxin’s Role in Fibrosis
Although no effective treatments currently exist for systemic sclerosis (SSc), new research on autotaxin, a key mediator of the lipid lysophosphatidic acid (LPA), may offer hope, said Flavia V. Castelino, MD, assistant professor of medicine at Harvard Medical School in Boston.
Autotaxin is highly expressed in the skin of SSc patients, along with high levels of IL-6, she said. LPA induction of autotaxin requires IL-6, and this loop leads to fibroblast formation, subsequent extracellular matrix deposition and collagen accumulation in these patients, she said.
Dr. Castelino’s team studied autotaxin’s role in localized LPA production and SSc fibrosis. Mice received four subcutaneous injections of bleomycin over 28 days, and they expressed autotaxin after three days. Using a novel autotaxin inhibitor called PAT-048, they found that the drug abrogated bleomycin-induced dermal fibrosis and also reduced hydroxyproline content. The drug also attenuated IL-6 production in the skin of these mice, she said. The LPA-autotaxin-IL-6 loop is a potential target for developing new SSc therapies, she said.
Post-Transplant Mortality
Many transplant programs are reluctant to offer lungs to adults with SSc due to concerns about extrapulmonary involvement that may affect their survival. However, according to a retrospective cohort study published in 2014, adults with SSc had one-year mortality risk that was comparable to patients with pulmonary arterial hypertension (PAH), a widely accepted indication for lung transplantation, said Elana J. Bernstein, MD, MSc, instructor at Columbia University College of Physicians and Surgeons in New York City.
Dr. Bernstein and her colleagues collected survival rates for 3,763 adults with SSC, PAH and interstitial lung disease (ILD) from the UNOS database. After fully adjusting the rates to account for other factors that may influence mortality, they found that SSc patients had a 48% higher risk of death than ILD patients, but comparable risk to PAH patients. Further stratified analyses showed that SSc patients who did not take preoperative corticosteroids also showed a higher mortality rate than those with ILD or PAH. “One possible explanation for this finding is that corticosteroid use might attenuate the risk associated with the diagnosis of systemic sclerosis,” said Dr. Bernstein. The analysis was limited due to the lack of some information, such as phenotypic profiles, in this database, but may help identify modifiable risk factors for SSc patients who seek lung transplants in the future, she said.
Anti-Ro52 & Innate Immunity
Interaction between anti-Ro52 antibodies and innate immunity may play a critical role in Sjögren’s syndrome induction, according to research presented by Umesh S. Deshmukh, PhD, an associate at the Oklahoma Medical Research Foundation in Oklahoma City. The presence of anti-Ro52 antibodies is associated with a higher severity of disease in Sjögren’s syndrome in mice, he said. How does the immune response against Ro52 influence disease pathogenesis? That’s not yet known, he said.
One injection of alum causes a significant reduction in saliva production in mice, Dr. Deshmukh noted. His team found that immunizing New Zealand Mixed 2758 mice, bred with a genetic susceptibility for a Sjögren’s-like disease, against Ro52 with alum generated a robust Ro52 antibody response compared to mice injected with maltose-binding protein and alum or alum alone, he said. Salivary gland function was diminished. “If you measure pilocarpine-induced saliva production in these mice, the Ro52-immunized mice show the highest significant drop in their ability to make saliva,” Dr. Deshmukh said. “Also, the mice with the highest anti-Ro52 reactivity had the lowest ability to make saliva.”
Both the Ro52-immunized mice and the mice receiving the MBP and alum showed mild sialoadenitis. Immunoglobulin gamma (IgG) deposits were seen in the salivary glands of the Ro52-immunized mice, but not in the other two groups, “suggesting that maybe some of these autoantibodies were actually penetrating the ductal cells” of the glands, he said. “Maybe you need prior action of innate immunity, and then maybe the antibodies become pathogenic.”
IDO & Neurotoxicity
Interferon-induced expression of the IDO gene is associated with neurotoxicity and may be one cause of severe fatigue and depression in primary Sjögren’s syndrome patients, said Naomi I. Maria, a graduate student at Erasmus MC in Rotterdam, The Netherlands.
There is a prevalence of IFN signature in the CD14 monocytes of primary Sjögren’s syndrome patients, she said. These patients also show higher disease activity scores and expression of antibodies like SSA, SSB and IgG, Ms. Maria said. IFN may also induce IDO expression, and increased IDO may result in reduced tryptophan and increased kynurenine. IDO may also suppress effector T-cell function and promote Treg differentiation.
To find out if IFN-induced IDO results in increased neurotoxicity that causes severe fatigue and depression, “we decided to look locally into the glands of these patients,” said Ms. Maria. “We found nice IDO expression in the glands, as well as MxA, and we had previously identified MxA as a good biomarker for interferon type-1 activity.”
These patients also showed higher levels of KAT neuroprotective enzymes and lower levels of KMO neurotoxic enzymes that are key players in the kynurenine-tryptophan pathway. They also showed upregulated Treg cells. Blocking that pathway may help prevent kynurenine from crossing into the brain and triggering fatigue and depression symptoms in these patients. Recent research suggests that exercise may increase KAT enzymes in muscle tissue, building resilience to stress-induced depression, she said.
Susan Bernstein is a freelance medical journalist based in Atlanta.
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