Complex, but common
Editor’s note: ACR on Air, the official podcast of the ACR, dives into topics important to the rheumatology community. Here we highlight episode 86, “Insights into Inborn Errors of Immunity,” which featured an interview with Dr. Bharat Kumar, physician editor of The Rheumatologist and aired on Sept. 24, 2024.
Rheumatologists often treat patients with complex systemic symptoms that can be hard to diagnose. Inborn errors of immunity are a differential diagnosis; these may present with autoimmunity, autoinflammatory issues and immunodeficiency, all mimicking rheumatic diseases.
A Terminology Debate
Dr. Kumar
One reason inborn errors of immunity can get complex is because the terminology used to define them continues to evolve, Dr. Kumar said. He cited the 2019 consensus definition: “The inborn errors of immunity, also referred to as primary immune deficiencies, manifest as increased susceptibility to infection, disease, autoimmunity, autoinflammatory disease, allergy and/or malignancy.”1 However, he noted, this definition does not offer much to indicate what these conditions are.
The terminology also can be misleading because not all of these inborn errors of immunity are present at birth. They can present later in life. Plus, a person can have an inborn error of immunity, but if they’re raised in a totally sterile environment, it may never manifest.
Dr. Kumar also does not like the use of the word error in the terminology. “Many of the things we’ve considered errors in the past have turned out to be natural human variation, or it’s turned out that they’re actually beneficial for whatever reason,” he said.
Even the term primary immune deficiency is not as precise as it could be, Dr. Kumar added.
Despite any misgivings about the terminology, Dr. Kumar believes that an awareness of inborn errors of immunity is important. “We’re learning the immune system is intimately involved in virtually every single physiological process, and that’s why rheumatologists should be aware of what inborn errors of immunity are,” he said.
When to Consider Inborn Errors of Immunity
Dr. Kumar said he sees about 50 patients a week. Among these, about two to three patients will have some immune deficiency requiring treatment.
The podcast host, Jonathan Hausmann, MD, a pediatric and adult rheumatologist in Boston, asked Dr. Kumar to share examples of when rheumatologists should think about inborn errors of immunity.
Dr. Kumar shared a few tips:
Family history: Ask about a family history of immune deficiency. A patient may respond with something like, “Oh yes, my brother was tested for this, and he had a mutation in this gene.” If you don’t get information that readily, you can ask such questions as, “Do you have family members who died of infections really early?” or “What types of diseases run in your family?”
“If there’s a very strong family history of, say, lupus, we know there are genetic mutations and that complement deficiencies confer a great deal of susceptibility for lupus,” Dr. Kumar said.
Recurrent infection: Another area to consider is whether the patient has recurrent infections—for example, multiple ear infections in adults without a structural reason or two or more sinus infections in a year, but doesn’t have allergies. “It’s not just the recurrent nature of these infections, but also the severity,” he said. An example of this severity could be a 30-year-old patient who is fine and then ends up quickly in the intensive care unit for an adenovirus infection.
Also, rheumatologists should watch out for severe autoimmune cytopenias, such as a patient with rheumatoid arthritis who goes on methotrexate and develops a surprising number of infections.
Chronic diarrhea: Another warning sign is chronic diarrhea with weight loss because many conditions within immune deficiency have this symptom. “Alternately, chronic diarrhea could be causing a loss of certain types of immunoglobulin and, therefore, causing more immune deficiency,” he said.
Example
Paying close attention to a patient’s history is important. Dr. Kumar shared the example of a patient who had a positive anti-nuclear antibody of 1:160 and was seen for what was thought to be fibromyalgia. Going further into the patient history, Dr. Kumar found the patient had a history of previous sinusitis that was just described as allergies, but she had never been tested for allergies.
“As I was taking the history, I didn’t hear anything that sounded strongly allergic in nature,” he said.
The patient mentioned that when she went to the grocery store, she would put things in her cart and as she pushed further with the cart, her hands would start to cramp. This experience didn’t seem to fit a typical explanation of fibromyalgia, Dr. Kumar said.
Her nails also had a dystrophy common in recurrent fungal infections.
He ordered some tests, including one for calcium. The laboratory results revealed the patient’s calcium was low enough to warrant hospitalization.
They discovered she had a subclinical variant of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
It’s not always easy to identify inborn errors of immunity.
“We were able to get a diagnosis because we were thinking a little bit outside the box,” he said. “I wish I could provide an easy mnemonic for immune deficiencies. Unfortunately, I can’t. But there are a lot of different conditions out there that can mimic immune deficiencies, and many of them are rheumatological in nature.”
Patient Management
According to Dr. Kumar, treatment for patients with inborn errors of immunity may include the following:
- Subcutaneous immunoglobulin for those with antibody-mediated disorders;
- Recurrent antibiotics: “This is something that’s fallen out of favor for very good reason, but it’s useful for people who are getting antibiotics anyway on a very frequent basis,” he said. “So [ordering antibiotics] ahead of time instead of afterward may not be a bad idea.” Suppressive antivirals and antifungals also fall under this umbrella;
- Biologic medications: Some genetic mutations are amenable to certain types of biologics, he noted;
- Stem cell transplants and chimeric antigen receptor T cell (CAR T) therapy: Although not routine, this approach could be used more often in the future, Dr. Kumar said.
If a patient with arthritis or another rheumatic condition has an inborn error of immunity, they should be seen by both a rheumatologist and a clinical immunologist, Dr. Kumar advised. The two specialists can negotiate where each one feels comfortable offering treatment.
If it’s of interest to the physician, a dual certification in allergy/immunology and rheumatology—which Dr. Kumar has—is a useful way to truly understand these specific patients.
Rheumatologists and immunologists should help ensure this patient group stays up to date on preventive measures, including getting vaccines and performing frequent handwashing. However, be mindful that live vaccines should not be used with certain immune deficiencies.
Vanessa Caceres is a medical writer in Bradenton, Fla.
Reference
- Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee . J Clin Immunol. 2020 Jan;40(1):24–64.
