November 10-15

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Year in Review highlights top clinical, basic science papers


4 minutes

Jinoos Yazdany, MD, MPH
Jinoos Yazdany, MD, MPH

From lupus to COVID-19, 2020 has seen a flurry of practice-changing clinical research, including positive trial results involving lupus and data about the only agent shown to reduce mortality in COVID-19.

Jinoos Yazdany, MD, MPH, opened the Year in Review with a look at the top clinical science papers during the Opening Session on Thursday, Nov. 5, and Richard Bucala, MD, PhD, followed with a review of the year in basic science. Registered ACR Convergence 2020 attendees have on-demand access to watch a replay of the session through Wednesday, March 11.

The TULIP 1 and 2 trials of anifrolumab, an investigational blocker of all type 1 interferons, showed significant improvements in one-year BICLA-based Combined Lupus Assessment and reductions in steroid use vs. placebo in patients with systemic lupus erythematosus (SLE). A two-year trial of belimumab in lupus nephritis showed modest but clinically significant improvement in renal measures vs. placebo.

Richard J. Bucala, MD, PhD
Richard J. Bucala, MD, PhD

“Lupus trials have been severely challenged by endpoints,” said Dr. Yazdany, Alice Betts Endowed Professor at the University of California, San Francisco and chief of rheumatology at Zuckerberg San Francisco General Hospital. “If anifrolumab is approved by the Food and Drug Administration, it will enter the drug rotation for patients with active lupus.”

Another key finding noted by Dr. Yazdany: Lower doses of corticosteroids can reduce the incidence of severe infection without adversely affecting ANCA-associated vasculitis or rheumatoid arthritis flares for many patients.

Other studies addressed maintenance therapy. Patients with axial spondylarthritis in remission can reduce certolizumab dosing from every two weeks to every four weeks without increasing their risk of flare. And rituximab can be used as maintenance therapy to maintain remission of ANCA-associated vasculitis.

Several studies focused on patient safety:

  • An observational study of 196,129 women found that Asian women taking bisphosphonates are at elevated risk for atypical femur fractures compared to white women, underscoring the need for periodic drug holidays.
  • Methotrexate slightly increases the risk of skin cancers among rheumatoid arthritis patients, while long-term colchicine use may provide cardiovascular benefits for patients with gout and other high cardiovascular risk groups with rheumatic disease.
  • Tocilizumab and etanercept have similar cardiovascular event rates, while tocilizumab may slightly increase infection risk and gastrointestinal perforations.

In spondyloarthritis, the IL-23 inhibitor guselkumab improved active psoriatic arthritis vs. placebo with no major safety signals. The JAK inhibitor upadacitinib significantly reduced symptoms vs. placebo, offering the first oral option beyond nonsteroidal anti-inflammatories.

And of all the drug trials for COVID-19, dexamethasone remains the only agent with a proven mortality benefit in hospitalized patients. The steroid is most effective in patients on mechanical ventilation, less effective in those on oxygen therapy, and has no benefit in less severely ill patients.

The biggest news in basic science was high-dimensional profiling by single-cell RNA-sequencing. The technology is intrinsic to many of the most important basic science papers of the past year.

“This technology is revealing new clues to pathogenesis and progression of disease, as well as some insights into possible new therapeutics,” said Dr. Bucala, Waldemar Von Zedtwitz Professor of Medicine and Professor of Pathology and of Epidemiology, Yale School of Medicine.

Single-cell sequencing of pathogenic autoantibody-producing B cells revealed new oncogenic mutations in cells that produce pathogenic rheumatoid factor. These oncogenic pathways are an accumulation of multiple pathogenic somatic mutations over time.

“Mutations acquired over time suggest a role for environmental exposures in the development of cancer risk in rheumatologic disease, such as lymphoma seen in Sjögren’s syndrome, as well as pathogenic rheumatoid factor,” Dr. Bucala said.

An analysis of B cell receptors across lupus, Bechet’s, Crohn’s, ANCA-associated vasculitis (AAV), EGPA, and IgA vasculitides found that IgA is overrepresented in all of the conditions except AAV and EGPA. The findings underline the importance of mucosal immunity in driving most of these conditions.

The major histocompatibility complex on chromosome six is the most variable region in the human genome and among the most densely packed with expressed genes. Whole-genome sequencing found that a higher Complement C4A copy number was associated with reduced SLE risk. There is a stronger C4 allele effect in men than in women, which may contribute to the increased incidence of lupus in women.

New findings in Notch signaling reveal that communication between endothelial cells and perivascular fibroblasts in the joint synovium mediates differentiation, expansion, and inflammatory phenotype in rheumatoid arthritis. Targeting the signaling pathway could alter the progression of joint destruction.

Also in RA, distinct subpopulations of synovial macrophages are associated with both remission and active disease flares. These populations may represent novel therapeutic targets.

A long-term study of home-sampled fingerstick blood identified a specific population of pre-inflammatory mesenchymal, or PRIME, cells that appear in circulation before an RA flare. These PRIME cells likely traffic to the synovium to perpetuate inflammation and can function as a biomarker to predict flare.