Sunday morning’s Year in Review session brought together two experts who culled research published over the past year in clinical and basic science to selected studies they felt showed major trends and significant insights to the development and treatment of rheumatologic diseases, including rheumatoid arthritis, osteoarthritis, and lupus.
Ingrid E. Lundberg, MD, PhD, Professor and Senior Consultant in Rheumatology at the Karolinska University Hospital and the Solna and Karolinska Institute in Stockholm, Sweden, said, “In rheumatic diseases, we see a shift in research focus from established disease to what I call pre-disease, that is, early cases and cases in those who still don’t have the disease.”
Research over the past year suggests that rheumatic diseases may start long before classic features of the disease are present in patients.
“By studying early cases, we can learn more on pathogenesis that is important in the development of new therapies,” Dr. Lundberg said.
Because rheumatologists need to treat RA early in the course of the disease, this shift in research is important. Dr. Lundberg presented studies showing that ultrasound imaging can predict progression to arthritis in patients who are ANCA positive without clinical signs of synovitis. In addition, evidence of subclinical inflammation on MRI for patients with suspected RA can predict the development of clinical arthritis.
Dr. Lundberg also addressed research indicating that environmental factors, namely smoking and older age, are associated with a high risk of developing joint pain in patients with inflammatory signs of arthritis.
In individuals with established hand osteoarthritis, ultrasound used to detect inflammation can predict the development of erosions in joints and progression of disease, according to recent studies, she said.
Studies of a promising new drug, tocilizumab, a monoclonal antibody against interleukin-6, for the treatment of giant cell arteritis and polymyalgia rheumatica, indicate that this new agent may be safe and effective in the induction and maintenance of disease remission.
Phase 3 investigations of another new drug, baricitinib, an oral Janus kinase 1 and 2 inhibitor, have demonstrated that in patients with RA who have an inadequate response to biologic DMARDs, baricitinib was associated with clinical improvement at 12 weeks, Dr. Lundberg said.
Basic Science Research
Bruce N. Cronstein, MD, the Paul R. Esserman Professor of Medicine and Director of Translational Medicine at the New York University School of Medicine, shed light on key basic science research published in the last year, including the role of mitochondria in the development of lupus and osteoarthritis and the use of genomics in understanding the underlying mechanisms of RA.
Mitochondria are initially present inside cells as micro-organisms that develop energy in the form of adenosine triphosphate (ATP). Subsequently, mitochondria are released into the extracellular space, where they induce an immune response, Dr. Cronstein said.
Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in patients with lupus. Interferon-alpha induces intramitochondrial retention of oxidized mitochondrial DNA (mitoDNA) in neutrophils. Intramitochondrial oxidized mitoDNA has been found in neutrophils from lupus patients, and lupus patients have antibodies to oxidized mitoDNA, he said.
“Neutrophil extracellular traps enriched in oxidized mitoDNA are interferogenic and contribute to lupus-like disease,” he said.
Oxidized mitoDNA stimulates interferon-alpha production. Lupus patients have antibodies to oxidized mitoDNA and an enhanced interferon-alpha signature.
“Interferon-mediated dysregulation of mitochondrial disposal contributes to autoimmunity in lupus and fills out some of the details that have been missing in our understanding how interferon contributes to the pathogenesis of lupus,” he said.
In patients with OA, chondrocytes from aging and osteoarthritic cartilage produce less ATP and diminish mitochondrial function. Loss of mitochondrial function precedes cartilage injury and further diminishes ATP production and the capacity to resist inflammatory changes.
“Mitochondrial dysfunction leads to chondrocyte catabolism and cartilage loss,” Dr. Cronstein said.
Genomic studies of RA suggest that joint-specific DNA methylation and transcriptome signatures in RA patients identify distinct pathogenic processes. Analyses of DNA methylation patterns have shown joint-specific patterns in RA and OA.
Different inflammatory pathways appear to be activated in knees and hips in RA. This finding may explain the involvement of different joints at different times during the disease process and the differentia responses to therapies in different joints, he said.