COPA Syndrome: What Do We Know About This Rare Disease?

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ACR CONVERGENCE 2020—Tiphanie Phillips Vogel, MD, PhD, assistant professor of pediatrics and internal medicine at Baylor College of Medicine, Houston, moderated the session on COPA syndrome, which drew 324 attendees on a Sunday morning. This rare genetic cause of immune dysregulation can present like anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, lupus, lupus nephritis or rheumatoid arthritis with interstitial lung disease.

Afterward, she spoke with The Rheumatologist. “There’s no chance this is as rare as is currently reported,” emphasizes Dr. Vogel, who believes many cases of COPA syndrome are undiagnosed. She does not want rheumatologists to miss the diagnosis. She hopes the session prompted clinicians to ask themselves, “I wonder if I have a COPA syndrome patient in my clinic?”

Presentation

Patients who develop symptoms of COPA syndrome always have lung disease, approximately half have inflammatory arthritis, and a quarter have glomerulonephritis. Diagnosing the syndrome can be confusing, because the mutation does not have 100% penetrance, meaning some carriers of the COPA mutation have no symptoms. These overlapping patient presentations can be puzzling, says Dr. Vogel.

During the session, she described the first patient she saw with COPA syndrome: The patient presented as a teenager, with pulmonary hemorrhage—a phenomenon experienced by approximately half of patients with COPA syndrome—and glomerulonephritis. The family was known to the hospital because the patient’s brother was being treated for juvenile idiopathic arthritis (JIA). Additional family history was significant for several relatives with rheumatoid arthritis.

This family history prompted genetic testing and revealed the family has COPA syndrome. When the treatment team circled back to examine the lungs of the brother with JIA, they found that although he was not known to have lung disease, he did, indeed, have it, but the disease was not as severe in his case as in his sister’s.

Dr. Vogel has published on this family.¹ Her reports join others to document a total of 48 patients. Her team is currently at work on a literature review of these patients and their treatment, but Dr. Vogel points clinicians who are eager to learn more now to a review published in the April issue of the Journal of Clinical Immunology.²

Although half of COPA syndrome patients develop their first symptoms when they are younger than 5 years old, approximately 10% of patients first present as adults.

She describes three typical presentations of a patient with COPA syndrome. The first is a young patient (including toddlers) with early onset of pulmonary hemorrhage. The second is a teenager with interstitial lung disease whose family history includes individuals with rheumatoid arthritis. This describes the above-described COPA syndrome patient at Baylor. The third presentation that should raise the index of suspicion for COPA syndrome is a family of individuals with vasculitis. Dr. Vogel emphasizes that familial vasculitis is highly unusual.

These three presentations underscore the importance of obtaining a thorough family medical history. Given the prevalence of rheumatoid arthritis, Dr. Vogel says rheumatologists may be inclined to dismiss the presence of rheumatoid arthritis in a patient’s family as an indicator of a COPA mutation. However, nearly two-thirds of COPA syndrome patients are rheumatoid factor positive. Therefore, because COPA syndrome patients can have undiagnosed lung involvement, she urges rheumatologists to let the presence of a family history of rheumatoid arthritis trigger suspicion of COPA syndrome in patients with interstitial lung disease.

If a clinician suspects a patient has COPA syndrome, the patient should be sent for genetic sequencing. Any exome sequencing, although expensive, will find a COPA mutation. Dr. Vogel identified several companies that have COPA on their genetic panels, and these tests can be more reasonable (for example, $250 out of pocket). These companies include Invitae, Fulgent Genetics and PulmZoom.

Dr. Vogel explains that a diagnosis of COPA syndrome is important because it changes disease prognosis for children. Often pediatric rheumatology patients can achieve long-term remission, but patients with COPA syndrome may not be able to achieve sustained remission without medication. In addition, because COPA syndrome is a genetic disease, patients should be referred to a genetic counselor, something Dr. Vogel does when her patients become sexually active or head off to college.

Treatment

Lastly, patients diagnosed with COPA syndrome tend to be treatment resistant such that most patients with COPA syndrome have tried and failed four or more medications. A number of COPA syndrome patients have progressed to lung or kidney transplant, or needed joint replacements for severe arthritis.

A diagnosis of COPA syndrome may point to additional treatment options. Dr. Vogel’s group and collaborators, including rheumatology fellow Leigh Anna Stubbs, MD, MPH, presented an abstract at ACR Convergence 2020 indicating that rituximab may be a good option for these patients.³

Other rheumatologists have noted the interferon signature of patients with COPA syndrome and treated them with a Janus kinase 1/2 inhibitor. One case report of a 15-year-old girl found this approach stabilized disease for months.⁴

A Growing Concern

COPA syndrome is currently considered a rare disease, but Dr. Vogel believes that as rheumatologists better understand the presentation of COPA syndrome, the diagnoses will increase and its status as an ultra-rare disease may change.

As an ultra-rare disease, COPA syndrome suffers from the curse of most rare diseases: low patient numbers and a lack of diagnosis that leaves studies underpowered. Because of this, most rare diseases enter the medical literature as case studies or case series—reports that, according to Dr. Vogel, most rheumatology journals don’t consider. She remains determined to spread the word about COPA syndrome, stating, “We have to get these one-off stories out there so other clinicians know what to do.”

Absent a clear path to publication in rheumatology journals, she anticipates more COPA syndrome cases will be published in clinical immunology journals, which are more likely to embrace rare cases. However, Dr. Vogel stresses that COPA syndrome patients will be treated in rheumatology clinics, so rheumatologists need to be aware of these rare patients.

Difficulty recognizing rare disease can lead to an interesting question: Is COPA syndrome “a genetic mimic of rheumatic disease” as it is labeled in the scientific session, or is it a rare rheumatic disease, one that has not yet been fully recognized by the rheumatologic community? Perhaps it is a matter of perspective.

Dr. Vogel believes that “COPA mutations cause COPA syndrome, which can look like lupus, vasculitis or rheumatoid arthritis with interstitial lung disease.”

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

References

1. Cabrera-Pérez JS, Branch J, Reyes A, et al. A zebra at the rodeo: Dyspnea, hematuria, and a family history of arthritis. Arthritis Care Res (Hoboken). 2020 Jun 29. Online ahead of print.
2. Frémond M-L, Crow YJ. STING-mediated lung inflammation and beyond. J Clin Immunol. 2021 Apr;41(3)501–514.
3. Stubbs L, Osuna I, Bigley T, et al. Use of rituximab to treat COPA syndrome: A multi-institutional cohort [abstract 1166]. Arthritis Rheumatol. 2020 Oct;72(suppl 10).
4. S Krutzke, C Rietschel, Gerd Horneff. Baricitinib in therapy of COPA syndrome in a 15-year-old girl. Eur J Rheumatol. 2019 Aug 20;7(Suppl 1):1–4.