Year in Review session previews potential of new, engineered treatment pathways

Messenger RNA (mRNA) vaccines against COVID-19 are the early steps in what could be a new wave of engineered RNA and genomic therapeutic agents, both injectables and implants that autoregulate production of anti-cytokine and other drugs to treat rheumatic diseases.

“We have proof of concept in mice. We don’t know yet if they will translate to humans, but they are very intriguing,” said Michael Brenner, MD, the E.F. Brigham Professor of Medicine at Harvard Medical School and Director of the Human Immunology Center and the Single Cell Genomics Core at Brigham and Women’s Hospital.

Dr. Brenner discussed a noninflammatory mRNA vaccine that induces tolerance to treat multiple sclerosis in a mouse model, as well as a bioartificial organoid that secretes IL-1 receptor agonist (IL-1Ra) to treat serum transfer arthritis in mice during the basic science portion of the 2021 Year in Review session on Friday, Nov. 5. The session can be viewed by registered meeting participants through March 11, 2022.

The two current mRNA COVID-19 vaccines elicit an inflammatory response to protect against severe disease, Dr. Brenner said. A similar approach has been applied to a noninflammatory mRNA vaccine to treat experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The noninflammatory vaccine replaces uridine with N1-methylpseudouridine during mRNA synthesis to induce immune tolerization.

“Being able to use mRNA technology either for immune stimulation or immune tolerization could reopen efforts in antigen-specific immunotherapy,” Dr. Brenner said. “It has immense application to autoimmune, allergic, and transplantation conditions.”

A novel bioartificial implant uses engineered induced pluripotent stem cells (IPSC) to produce differentiated chondrocyte-like cells contained within a small subcutaneous organoid. The modified chondrocyte-like cells produce IL-1Ra in an entirely autoregulated manner. The secreted IL-1Ra significantly reduced pain scores and virtually eliminated bone damage in induced arthritis.

“Our future may have in it other bioengineered implants,” Dr. Brenner said. “It is a very exciting prospect for drug development and delivery.”

Dr. Brenner also discussed basic science findings from the past year linking the 2021 Nobel Prize in Physiology and Medicine to the role of IL-1 in inducing chondrocyte hypersensitivity in osteoarthritis; a new autoinflammatory disease, VEXAS, created by somatic mutations in the ubiquitin-proteasome system; the previously unknown role that red blood cells containing mitochondrial DNA play in lupus; and the key role type 1 interferon autoantibodies play in the development of life-threatening COVID-19, especially in males.

Karen H. Costenbader, MD, MPH, reviewed key clinical research findings from the past year.

“A new day is dawning in rheumatic diseases,” said Dr. Costenbader, Director of the Lupus Program at Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School.

The Food and Drug Administration approved avacopan, a new oral C5a inhibitor for adults with severe ANCA-associated vasculitis. The agent showed clear superiority to placebo as an add-on therapy (p=0.007) and reduced the risk of relapse (HR=0.046). And voclosporin, a new oral calcineurin inhibitor, was approved for adults with active lupus nephritis as an add-on based on complete renal response at 52 weeks (HR=2.65, p<0.0001).

The Janus Kinase (JAK) inhibitor tofacitinib failed to show non-inferiority versus anti-TNF therapy in an FDA-mandated post-approval study in ankylosing spondylitis. All JAK inhibitors now carry a new black box warning for increased risk of serious cardiovascular events, thrombosis, malignancy, and mortality.

Stable dosing beats half-doses of conventional DMARDs for preventing rheumatoid arthritis flares for patients in remission (HR=4.0). The new ARCTIC REWIND findings are reflected in the ACR’s 2021 guideline for the management of RA.

The open-label TICOSPA trial found that treat-to-target versus usual care in axial spondyloarthritis does not significantly improve Assessment of SpondyloArthritis international Society (ASAS) criteria scores at 48 weeks, but does improve quality of life and saved about $545 per patient in treatment costs.

And a stepped exercise program for Veterans Administration patients with knee osteoarthritis significantly decreased perceptions of pain and improvement in function but did not affect objective physical function tests compared to arthritis education.

An observational cohort study using data from the ACR Rheumatology Informatics System for Effectiveness (RISE) registry confirmed significant disparities in functional status for patients living in poor neighborhoods. And a new machine learning analysis of knee X-rays may reduce racial and socioeconomic disparities in knee arthritis pain by better identifying patients more likely to benefit from knee arthroplasty.

The U.S.-based Overcoming COVID-19 study concluded that intravenous immunoglobulin plus glucocorticoids reduces cardiovascular dysfunction better than glucocorticoids alone, while the international BATS Study found no difference in outcomes. Dr. Costenbader speculated that differences in populations, treatment timing, and other factors may account for the conflicting results.

Observational data also showed that in people with rheumatic diseases, glucocorticoid doses >10 mg/day, moderate/high rheumatic disease activity, and multiple immunosuppressant medications are all associated with an increased risk of death from COVID-19. And, not surprisingly, individuals on immunosuppression show reduced immunogenicity following mRNA vaccines against SARS-CoV-2 infection.