Reverse Translation in Advancing Pharmacotherapy in Pediatric Rheumatology: A Logical Approach in Rare Diseases with Limited Resources

Reverse translation, defined here as the use of clinical observations to drive scientific investigation, has been used in the field of Pediatric Rheumatology for decades. Forced in part by limited resources and rare childhood diseases, clinical questions have driven scientific investigation and have focused basic science research efforts to address the most clinically relevant questions. Here we discuss the application of reverse translational approaches, by us and others, to improve pharmacotherapy in Pediatric Rheumatology. Pediatric Rheumatology is a field focused on treating autoimmune and autoinflammatory diseases in childhood. With 300 pediatric rheumatologists in North America, and entire states without representation, it is appropriate to say that the clinical need in Pediatric Rheumatology is underserved. However, despite the inherent challenges in caring for a rare pediatric patient population, great strides have been made in advancing the field through scientific discovery inspired by the multitude of questions naturally generated while providing routine clinical care. The concept of “reverse translation” is practiced every day, even at times unintentionally, in fields that let their clinical questions guide their research efforts. Furthermore, in subspecialties like pediatric rheumatology, which is based on a strong foundation of clinical diagnosticians, clinical variability becomes a natural driver for scientific discovery. Effective use of pharmacotherapy is critical to disease management in the treatment of the Pediatric Rheumatology patient population. However, clinical response to drug therapy can be highly variable, resulting in a trial-and-error approach to treatment that can have long-term deleterious consequences for the patient. These observations have fueled scientific investigation into factors impacting drug response and represents a reverse translational approach to improve patient outcomes through the early use of optimal drug therapy. We posit that three factors primarily contribute to the observed variation in drug response (Figure 1). These factors include heterogeneity in the underlying disease that can significantly impact how the patient responds to the particular drug therapy, pharmacokinetic variation resulting