What Rheumatologists Need to Know About the Management of Rare Diseases in Rheumatology

In light of Rare Disease Day 2023, Yusuf Yazici, MD, and Peter Grayson, MD, discuss the various aspects of rare disease research and management, including the associated challenges in diagnosis, treatment, and patient care.

Rare diseases in rheumatology are surprisingly common – there are approximately 7000 known “rare” rheumatic diseases, including myositis, vasculitis, and antiphospholipid disorders.1

Despite the high prevalence of rare diseases in rheumatology, small sample sizes and heterogeneity of these conditions have limited their review in randomized controlled trials.2 In addition, although 80% of rare diseases are genetic, limited data are available at a molecular level, which results in difficulty in accurately identifying these conditions.3

We spoke with clinicians specializing in the research and treatment of rare diseases to get further insight into how to manage and navigate the challenges associated with these conditions.

What to Know About Rare Diseases in Rheumatology

Providing Access to Care & Early Diagnosis Is Critical

Access to Care & Workforce Shortage

Yusuf Yazici, MD, clinical associate professor of medicine at the New York University School of Medicine, noted, “One of the main issues that rheumatologists face with rare conditions is the time it takes for the patient to [get access] to the doctor.”

In fact, patients may receive several rounds of medications at primary care centers before being referred to a specialist. Dr Yazici discussed the shortage of a rheumatology workforce in the US, which puts patients on a “waiting list” before they can be seen.

On the other hand, efforts are being taken to support primary care providers in the management of rheumatic and musculoskeletal diseases to decrease the demand for subspecialty consultation.4

In addition to the limited number of specialists in the country, not all rheumatologists specialize in rare diseases.

Time to Diagnosis

Further, patients with rare diseases typically do not show the entire spectrum of symptoms, which may result in a delayed time to diagnosis.2

Peter Grayson, MD, chief of the Vasculitis Translational Research Program and associate director of the Rheumatology Fellowship Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), recommends that patients with symptoms of rare and ultra-rare diseases be referred to a specialized academic or research center, such as the National Institutes of Health (NIH), where a differential diagnosis can be made.

Rheumatologists should pay attention to the “diagnostic odyssey” of patients with rare diseases, as a faster diagnosis can potentially prevent organ damage. Dr Yazici said, for example, uveitis is one of the most disabling complications of Behçet syndrome, a rare form of vasculitis, which can progress to blindness if untreated.5

Apart from improved speed, a personalized diagnosis is important in care management, which can be developed by using different treatment strategies based on the phenotype of patients.1

Rethinking Diagnostic/Classification Criteria

“Rheumatology as a community probably has the most number of diagnostic criteria tests compared with any other [specialty],” Dr Yazici noted, “and there are multiple versions, revised versions, and subcategory versions of these criteria for each disease.”

Rheumatology providers may be faced with the unique challenge of distinguishing between rheumatologic and nonrheumatologic conditions that present with similar manifestations and shared features.6 This emphasizes the need for clear diagnostic and classification criteria to help us understand disease pathogenesis and clinical practice. While some researchers believe there is a difference between diagnostic and classification criteria in clinical practice, Dr Yazici stated that there seems to be a lack of a formal distinction and that diagnosis based on criteria must be simplified.6

Strict adherence to diagnostic criteria, based on a set of presentation symptoms, could lead to over- or underdiagnoses of conditions. To that effect, Dr Grayson recommended against anchoring on an approximate diagnosis and premature closure for patients whose symptoms do not conform to these criteria, as maintaining a certain degree of uncertainty can be healthy.

In an article by rheumatologists Megan Milne, MD, and Rebecca E. Sadun, MD, awareness of cognitive biases in rheumatology has been described as an important first step for providers, followed by the adoption of debiasing strategies, to improve patient care.7

To sum it up, Dr Grayson alluded to rheumatologists as being the “diagnostic sleuths of medicine!”

Encouraging Clinical Trial Participation

Enrollment in clinical trials, especially for pediatric rheumatic diseases, has been one of the major barriers in rheumatology research, and thus, patient management.

Dr Yazici pointed out the difference in the number of head-to-head trials and sample sizes between common rheumatic conditions, like rheumatoid arthritis, and the rarer conditions in rheumatology.  Because of the limited pharmacotherapies that can be developed for patients with the rarer conditions, pharmaceutical companies lack financial incentive to conduct research, which some researchers call “the elephant in the room for improving care.”1 Dr Yazici also noted that it is important to remember that patients with rare rheumatologic conditions may be good candidates for experimental drugs, which can inform future research and therapy. 

Of note, findings from a systematic review and meta-analysis have indicated that for some rare rheumatic diseases, including systemic sclerosis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and Behçet syndrome, higher quality trials for pharmacotherapy have been conducted.2

Researchers have also suggested modifications, including the development of novel methodology, to existing trial designs to improve their efficiency and maximize the limited available data in rare diseases for continued research.8

Developing a Working Knowledge of Rare Diseases

Dr Grayson encourages rheumatology providers to have a good working knowledge of key rare diseases, including vasculitis, relapsing polychondritis, myositis, and connective tissue disease. He noted that “actively monitoring and being aware of the rare disease space” is valuable and can be made possible by attending sessions at annual rheumatology meetings. The value of clinical immunology/basic science is also underappreciated, but continuously engaging with educational resources on topics in rare diseases can result in better treatment decisions for patients, Dr Grayson said.

Using the example of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, Dr Grayson suggested that sharing and discussing complex cases among peers and clinicians may result in the realization that certain conditions and their clinical presentation may be more common than initially thought.8

Overall, clinicians are encouraged to adopt a more holistic approach in the care and management of patients with rare diseases.

Disclosures: Dr Yazici declared affiliations with Amgen, BMS.


  1. The Lancet Rheumatology. Long-awaited action on rare diseases. Published online April 2022. doi:10.1016/S2665-9913(22)00072-8
  2. Bender TTA, Leyens J, Sellin J, et al. Therapeutic options for patients with rare rheumatic diseases: a systematic review and meta-analysis. Orphanet J Rare Dis. 2020;15:308. doi:10.1186/s13023-020-01576-5
  3. Hay E, Elmslie F, Lanyon P, Cole T. The diagnostic odyssey in rare diseases; a Task and Finish Group report for the Department of Health and Social Care. Report. NIHR Open Research. Published online January 27, 2022. doi:10.3310/nihropenres.1115171.1
  4. Miloslavsky EM, Marston B. The challenge of addressing the rheumatology workforce shortage. 2022;49(6):555-557. doi:10.3899/jrheum.220300
  5. Ozyazgan Y, Ucar D, Hatemi H, Yazici Y. Ocular involvement of Behçet’s syndrome: a comprehensive review. Clinic Rev Allerg Immnunol. 2015;49:298-306. doi:10.1007/s12016-014-8425-z
  6. Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria? Arth Care Res. 2015;67(7):891-897. doi:10.1002/acr.22583
  7. Milne M, Sadun RE. How to avoid cognitive errors in rheumatology. The Rheumatologist. Published online March 14, 2022. Accessed on February 24, 2023. https://www.the-rheumatologist.org/article/how-to-avoid-cognitive-errors-in-rheumatology/
  8. Smith CT, Williamson PR, Beresford MW. Methodology of clinical trials for rare diseases. Best Pract Res Clin Rheumatol. 2014;28(2):247-262. doi:10.1016/j.berh.2014.03.004
  9. National Institutes of Health: NIH Research Matters. VEXAS syndrome more common than realized. Published online February 14, 2023. Accessed on February 24, 2023. https://www.nih.gov/news-events/nih-research-matters/vexas-syndrome-more-common-realized