2014 ACR/ARHP Annual Meeting: Rheumatologic Research Uncovers Clues to Therapies

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An intricate network of interconnecting pathways underlies the answers to how and why patients develop rheumatic diseases and who may respond to certain treatments.

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.