A canker sore—a painful white ulcer inside the mouth—might be brought on by stress. Or the wrong toothpaste. Or certain foods: tomatoes, peanuts, cinnamon. Or an iron deficiency. Or an allergy. Or a new prescription. Or an underlying autoimmune disease.

Even though millions of people suffer from them every year, researchers still don’t know much about what fundamentally causes these sores. This leaves doctors and dentists stuck playing detective with their patients—running down a checklist, trying to figure out which of more than a dozen potential triggers could’ve set off the gnarly little lesions.

That list is long and spans different specialties in medicine. It includes trauma to the mouth, stress, diet, genetics, hormones, allergies, vitamin deficiencies, autoimmune diseases, and gastrointestinal diseases. Diana V. Messadi, a professor at the UCLA School of Dentistry, told me that canker sores are multifactorial, which makes them hard to study. Cold sores, by comparison, offer a much tidier story: They’re viral infections (herpes simplex) and thus are treatable with antivirals. (Cold sores are pimplelike blisters that usually form around the lips, whereas canker sores are white ulcers that occur inside the mouth.)

Canker sores can be loosely sorted into two buckets. In Bucket A are the smaller, more common sores, the kind a person might get two or three times a year. These sores are bright, nagging, and painful, and they make eating and talking difficult. They usually aren’t life-threatening. In Bucket B are larger cankers, usually more than a centimeter wide. (Technically, a third bucket exists that includes herpetiform, or clustered, sores—but this type is rare.)

Big or small, some sores are linked to an underlying disease, like Crohn’s, Behçet’s, HIV/AIDS, or celiac disease. In a way, these cases are better understood: The sores are a secondary effect of something else going on in the body—something a doctor can test for and identify.

The human mouth is a weird place. Canker sores occur in what’s called the oral mucosa, which is doctor-speak for the skin (it’s not actually skin) inside your mouth. Even though the mucosa is tucked away inside your cheeks, it gets exposed to a lot. Salsa, notes Nasim Fazel, a former professor at UC Davis who started the college’s oral-mucosal clinic, “is a chemical irritant. You don’t rub salsa on your skin.” But people do eat salsa—and chips, nuts, and other foods that are spicy or acidic or sharp, and that can damage the lining of the mouth. Some of these wounds later develop into canker sores.

Because the mouth is dirty, white blood cells like to hang out there; Andres Pinto, a professor at the Case Western Reserve University’s school of Dental Medicine, told me that this way, they can react quickly to a potential infection. But sometimes, this surveillance system fails, and the body can actually self-injure. This is thought to be part of what causes typical canker sores, Pinto explained: Immune dysregulation is the “common denominator” behind the ulcers. Inflammation can help the body heal, but too much inflammation can cause the mucosa to break down, which is what we see when we look at the oval-shaped wounds.

Beyond that, canker sores are still idiopathic, meaning doctors don’t really know why they happen. The body’s immune system is deeply complicated; as my colleague Ed Yong wrote in 2020, it’s where “intuition goes to die.” “The problem with all these immune-mediated conditions, oftentimes, is we still don’t know why they come,” Alessandro Villa, the chief of oral medicine at the Miami Cancer Institute, told me. “At the end of the day, it’s still a big mystery.”

Another lingering mystery is why some people get canker sores while others live in ignorant bliss, free of their specific kind of torture. Genetics is starting to help solve that one. “Using sophisticated computers, we can actually detect which genes are associated with what we see in the mouth,” Pinto told me. “What I just said is a big step,” he added. “It took probably 30 years to develop that last sentence.”

More research is needed to better treat patients, especially those with bad or chronic sores. Topical steroids can help, but they don’t address the underlying causes. A spokesperson for the FDA told me there are no available FDA-approved prescription options specifically for canker sores.

Comparatively speaking, the United States does not have a lot of providers that specialize in this area. Fazel, formerly of UC Davis, is a rare combination of dentist and dermatologist who sometimes sees patients with debilitating cases. “I’m kind of using the same meds as I was using 10 years ago,” she told me. “It’s kind of sad.”

Oral-medicine specialists are dentists with extra training in such ailments. But only about 400 practice in the United States, Pinto estimated. A representative for the American Academy of Oral Medicine told me the organization currently has 281 active members (although it noted that there may be additional nonmembers practicing). Fazel, for her part, thinks dermatologists are better equipped to treat canker sores, because dentists “can’t prescribe the big guns.” (The “big guns,” in this case, are medicines that modulate the immune system to calm inflammation.) Even if a patient does manage to see the right provider, that’s only the first step. They’ll still need to go through the checklist, trying to determine what their triggers are—while the bigger question of what actually causes the sores remains unknown.

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