Youthful Exuberance: The Year in Review for Pediatric Rheumatology

Novel Diseases

Dr. Turnier went on to highlight several novel autoinflammatory diseases that are worthy of attention. Ubiquitylation—which is the addition of ubiquitylin to a protein substrate—has been recognized as a key mechanism in the regulation of immune responses. In fact, the “E” in VEXAS stands for E1 enzyme, the protein responsible for the first step in the ubiquitination pathway. Several “ubiquitinopathies” have been identified as a category of autoimmune disease, including OTULIN-related autoinflammatory syndrome (ORAS), a potentially fatal disease caused by a mutation in the OTULIN gene.

Davidson and colleagues describe the first heterozygous, dominant negative mutation that leads to loss of ubiquitinase activity in patients with ORAS. In two patients with this mutation, increased sensitivity to TNF-induced cell death was observed as was elevated type I interferon signature.⁴

In a different paper also related to a ubiquitinopathy, Oda and colleagues report on two patients with deficiency of SHARPIN, a component of the linear ubiquitin assembly complex (LUBAC). The authors found that SHARPIN loss of function mutations can lead to autoinflammatory symptoms and signs such as fevers, parotitis, arthritis, and colitis.⁵

Clinical Advances

Dr. Ruth

The second speaker in the session was Natasha Ruth, MD, MS, professor of pediatrics, division chief and program director, Pediatric Rheumatology, Medical University of South Carolina, Charleston, who provided updates in clinical advances from the past year (no small feat since by the year 2020 doubling time of medical knowledge has been estimated to be a mere 73 days).⁶

Dr. Ruth began by highlighting three clinical studies involving patients with juvenile idiopathic arthritis (JIA). The first study, carried out by the Pediatric Rheumatology InterNational Trials Organization (PRINTO) and The Pediatric Rheumatology Collaborative Study Group (PRCSG) investigators, looked at the efficacy and safety of subcutaneous tocilizumab in patients with polyarticular or systemic JIA. The investigators found that patients with these forms of JIA experienced long-term disease control with tocilizumab and that long-term safety was consistent with the known profile of this medication.⁷

The second clinical trial evaluated efficacy and safety of tofacitinib in patients with JIA and found that efficacy was maintained up to month 48 of follow up and that there were no deviations from the known medication safety profile.⁸

The third trial was from CLIPPER2, an eight-year, open-label extension of the phase 3b CLIPPER study of the safety and efficacy of etanercept in patients with JIA. In this study, one case of malignancy (Hodgkin lymphoma) was reported and the relationship of this cancer to etanercept or methotrexate could not be ruled out (though the overall observed malignancy rate was within that seen in patients with JIA who had not been exposed to TNF inhibitor therapy). The authors concluded that etanercept treatment for up to 10 years was well tolerated and had durable response in the patients still on active treatment.⁹