November 10-15

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Increased neuron pruning may be mechanism for CNS effects in lupus


3 minutes

Daniel H. Solomon, MD, MPH
Daniel H. Solomon, MD, MPH

The 2017 Year in Review on Sunday provided a quick overview of the best of basic science and clinical research papers from the past year.

Basic science presenter Richard M. Pope, MD, Solovy/Arthritis Research Society Professor and Professor of Rheumatology at the Northwestern University Feinberg School of Medicine, started with a look at a potential mechanism for the central nervous system (CNS) effects seen in type 1 interferon-mediated lupus. Microglia prune neurons to maintain a healthy CNS. In lupus, microglia become inflamed and prune neurons excessively.

Researchers noted that 564lgi mice with lupus-like disease exhibit behavioral characteristics that mimic psychological and social deficits seen in lupus. Interferon-alpha receptor (IFNAR) signaling regulates microglia activation and the increased phagocytosis of neurons. Treating these mice with an interferon receptor antibody down regulates IFNAR signaling and restores normal microglial activity. Similar activity was seen in human microglia from lupus patients.

“Under the influence of interferon, increased pruning of neurons may account for the CNS abnormalities seen in lupus patients,” Dr. Pope said.

A second lupus paper found that activating CD11b can suppress inflammation and autoimmunity. A novel molecule, LA1, reduces macrophage activation by suppressing interferon signaling along the AKT/FOXO3/IFR3/IRF7 axis and suppresses lupus-like disease in MRL/lpr mice.

Another paper proposed a mechanism driving fibrosis and interstitial lung disease in scleroderma. A familiar protein, Fli1 (Friend leukemia virus integration 1), is reduced in scleroderma keratinocytes and keratinocyte Fli1 knockout mice show scleroderma-like phenotypes. Fli1 knockout mice express increased systemic IL-6 and autoantibodies. The mice also develop dermal and esophageal fibrosis as well as interstitial lung disease. Similar Fli1-associated changes are seen in human lupus.

A new mouse model demonstrates the effect of adenosine on cartilage homeostasis and suggests that exogenous adenosine may inhibit the progression of osteoarthritis (OA). Knocking out the adenosine2a receptor promotes OA and restoring adenosine restores cartilage homeostasis.

On the clinical side, one of the major developments was the finding that genotype may better categorize juvenile idiopathic arthritis than phenotype, said Daniel H. Solomon, MD, MPH, Chief of Clinical Sciences, Professor of Medicine and Matthew H. Liang Distinguished Chair of Rheumatology at Brigham and Women’s Hospital and Harvard Medical School.

Oligo- and polyarthritis have similar HLA associations, and their genotype associations are similar to adult-onset rheumatoid arthritis. The ERA genotype is similar to spondylitis in adults while systemic JIA is distinct.

In the first in a series of drug trials, tocilizumab shows more than a 50 percent increase in remission in giant cell arteritis compared to oral corticosteroids alone.

Similarly, mepolizumab showed a six-fold higher rate of remission for eosinophilic granulomatosis with polyangiitis compared to placebo, a 70 percent reduced risk for relapse, and significantly less steroid use over 52 weeks.

On the cardiovascular (CV) side, IL-1β blockade with canakinumab can reduce second CV events as well as hospitalization, and urgent revascularization in patients with a prior myocardial infarction compared to placebo. Canakinumab also reduced infection, osteoarthritis, gout, and cancer mortality. Efficacy is based on reduction in inflammation, Dr. Solomon noted.

New data shows that celecoxib has similar cardiovascular safety as naproxen and ibuprofen. Celecoxib is more protective of the GI tract compared to the other agents and carries less risk for new onset hypertension.

Intra-articular steroids may not help OA treatment. Injecting triamcinolone was as effective as injecting saline in reducing pain and improving knee function, but steroids were associated with a reduction in cartilage thickness and a non-significant increase in total cartilage damage.

In psoriatic arthritis, tofacitinib is as effective as the TNF inhibitor adalimumab.

A phase 2 trial of tofacitinib versus placebo for axial spondyloarthritis found significant short-term efficacy and evidence of radiographic improvement. The adverse event profile was typical of tofacitinib, Dr. Solomon said, and the agent may move to a phase 3 trial.

A separate axial spondyloarthritis trial showed significant improvements in patient-reported outcomes from secukinumab.