Encoded by the Orphan Drug Act (ODA) in 1983, rare diseases are those that afflict less than 200,000 persons in the U.S. from infancy through adulthood. While “rare” may connote qualities separate from “common,” this should not marginalize rare diseases. In fact, rare gastrointestinal and hepatobiliary diseases are advancing our field in an ever-expanding manner with implications for patients, clinicians and researchers. Here, we will discuss how rare diseases illuminate conditions across a broad spectrum, impact health care utilization, promote training and mentoring, and how our partnerships with patients and families are transformational.
Rare diseases have enhanced our understanding of conditions such as inflammatory bowel disease (IBD) and eosinophilic gastrointestinal diseases. IBD encompass a spectrum of genetic contributions, from presentations in adults — where gene disruptions confer susceptibility — to much rarer presentations in infants when a single gene change may cause disease. Starting with the discovery of IL10 receptor defects, attention to these exceptional conditions has led to the characterization of an increasing array of molecular mechanisms of mucosal inflammation, including regulatory T cell (e.g., IL10R), phagocyte (e.g., G6PC3) and epithelial barrier (e.g., TTC7A).1 These breakthroughs, and their applications to therapeutic targets, have accelerated our understanding of IBD. Similarly, the emergence of eosinophilic diseases has brought forth the complexities of gastrointestinal antigen-immune responses and fostered dietary modifications as a treatment for eosinophilic esophagitis. Molecular studies have further defined eosinophilic esophagitis phenotypes with downstream clinical implications.2
At the core of rare diseases are the patients, and our partnership with them is germane to advancement of these diseases.
Though rare diseases affect a limited number of individuals, they may impact a disproportionate amount of health care resources, owing to both medical complexity and lack of clarity in optimal care. In addition, establishing a diagnosis requires ongoing testing, including initial evaluation and potential treatment of more common conditions. To address this imbalance, tools such as centers of excellence, expert consensus opinions and clinical guidelines help provide evidence-based care. In addition, ODA grants special “orphan designation” status to drugs, both small molecules and biologics, for rare diseases and provides various development incentives, including tax-credits. Nevertheless, innovative treatment strategies for rare diseases can be costly, as in chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory B-cell acute lymphoblastic leukemia.3 This study and the accompanying editorial discuss defining value for orphan drugs and further the conversations on aligning payer structures with clinical needs.3
Underlying our ability to move the field forward and further mature the care and study of rare diseases, it is imperative that we educate, mentor, coach and promote a cadre of learners, researchers, and leaders. Involving learners in the care of these patients strengthens GI training where residents and fellows gain insights into fundamental pathophysiologic principles and acquire the instinct to recognize unique disease states. In addition, rare diseases afford early career gastroenterologists opportunities for discovery in unexamined territories and accelerate career advancement. The Rare Disease Clinical Research Network (RDCRN) has 21 consortia studying more than 190 diseases, and works to improve rare disease understanding and awareness, in both the patient and medical communities. One such consortium, Consortium of Eosinophilic Gastrointestinal Diseases Researchers (CEGIR), has provided multicenter collaborations and cross-institutional mentorships that have accelerated the research of early-stage investigators and mobilized the necessary resources for robust clinical research.4
At the core of rare diseases are the patients, and our partnership with them is germane to advancement of these diseases. Patient advocacy groups, crucial to the enactment of the ODA, have been essential for awareness generation and fundraising; more than 280 patient advocacy groups form the National Organization of Rare Disorders (NORD) which serves as a central repository of information and efforts in rare diseases care. Many families acquire greater expertise in their rare condition than most of their health care providers, and this empowerment has carried fundamental advancements in enhancing their lives. In DGAT1 deficiency, for example, unremitting diarrhea from birth can necessitate TPN-dependence and early death. As children were identified by genetic testing, and families connected through online media, their collective experiences contributed to the identification of tailored dietary fat restriction as central to disease management.5 This citizen science outpaced any individual academic center, as the feedback and modifications occurred in real-time with a collaborative patient and family base. As a medical community, we must foster these opportunities while providing respectful oversight with attention to scientific rigor. The potential gains of patient-centered advancement of care are most impactful in rare diseases, but they could serve as models for common diseases as well.
In summary, rare diseases enrich our field. Their exceptional nature expands the bounds of our understanding, reveal fundamental aspects of basic pathophysiology, and inform core principles of treatment paradigms. Rare diseases are ever-evolving and evermore relevant for us to learn, teach and mentor.
- The study of rare diseases provides key insights into basic pathophysiology of human disease and carries broad implications for gastrointestinal and hepatobiliary health.
- Advocacy and thoughtful coordination of expertise and resources advance the care of rare diseases.
- Clinical and research training in rare diseases affords invaluable opportunities to transform multiple areas of our field.
- Patients and families are the core of rare diseases and may drive the largest impact of all.
Disclosures: Dr. Gupta serves as consultant to Abbott, Adare, Allakos, Receptos/Celgene, QOL, and has received research support from Shire/Takeda. Dr. Gupta is supported in part by CEGIR, part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED, CURED, and EFC. Dr. Picoraro has no conflicts to report.
1. Uhlig H.H., Schwerd T., Koletzko S., et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterol. 2014;147:990-1007.
2. O’Shea K.M., Aceves S.S., Dellon E.S., et al. Pathophysiology of eosinophilic esophagitis. Gastroenterol. 2018;154:333-345.
3. Whittington M.D., McQueen R.B., Ollendorf D.A., et al. Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia. JAMA Pediatr. 2018;172:1161-1168.
4. Gupta S.K., Falk G.W., Aceves S.S., et al. Consortium of eosinophilic gastrointestinal diseases researchers (CEGIR): Advancing the field of eosinophilic GI disorders through collaboration. Gastroenterology. 2019; 156:838-842.
5. Gluchowski N.L., Chitraju C., Picoraro J.A., et al. Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea. J Lipid Res. 2017;58:1230-1237.