A small but significant number of people with Lyme disease continue to suffer from symptoms long after finishing an antibiotic treatment. The mystery of why may have come closer to being solved with a study published Monday that found that bits of the Lyme bacteria can persist in patients’ inflamed joints even after taking antibiotics.

Lyme arthritis, the most common feature of the late-stage disease, leaves patients with swollen, painful joints. Researchers examining synovial fluid from those inflamed joints also found antibodies to the persisting molecules, called peptidoglycans, that come from the outer covering of the Lyme bacteria, according to the study, published in the Proceedings of the National Academy of Sciences.

That immune response “appears to be an important part of Lyme arthritis,” said the study’s lead author, Brandon Jutras, an assistant professor of biochemistry at Virginia Tech. “So, if we can prevent that response, we suggest that this could expedite resolution or eliminate symptoms entirely.”

People develop Lyme disease when a black-legged tick bites them and in the process transmits the bacterium Borrelia burgdorferi. Each year there are about 30,000 new cases of Lyme diagnosed in the U.S., according to the Centers for Disease Control and Prevention. Most cases are treated successfully with antibiotics, but if left untreated, the infection can spread to the joints, heart and nervous system. Even among those who get treatment early, several weeks of antibiotics don’t always result in a complete resolution of symptoms.

Post-treatment Lyme disease syndrome, the term doctors and researchers prefer over chronic Lyme disease, has been a subject of controversy for decades. Initially, some doctors suggested that patients were imagining their symptoms. But recent studies have found evidence of significant changes in the bodies of PTLDS patients. What’s not known yet is whether PTLDS symptoms are being driven in some cases by bacteria that didn’t get wiped out by antibiotic treatments or by persistent immune system changes that the disease caused — or both.

“We’ve gone from not knowing anything about the condition, to not knowing if patients really have symptoms, to knowing they really are sick,” said Armin Alaedini, an immunologist and assistant professor of medicine at Columbia University. “The work in my lab over the past 10 years on PTLDS shows that something is going on with the immune system. We see objective markers indicating the persistence of inflammation.”

Scientists estimate that 10 to 20 percent of patients diagnosed and treated for Lyme continue to suffer symptoms such as arthritis, brain fog, pain and fatigue.

While Jutras’s work focused on Lyme arthritis, it’s entirely possible that the findings may apply to other lingering Lyme symptoms.

“Whenever and wherever the bacteria grow, they shed peptidoglycan, so it seems plausible that it may be important in other late-stage Lyme manifestations,” Jutras said.

The new findings “could be an important new insight into Lyme arthritis and maybe other outcomes of infection with Borrelia burgdorferi,” said Mark Soloski, an immunologist and a professor of medicine at the Johns Hopkins School of Medicine and co-director for basic research for the Johns Hopkins Lyme Disease Research Center, who like Alaedini was not involved in the new study.

Soloski’s own research points to immune system malfunctions. “Our patients showed inflammation in unique regions of the brain, which suggests an immune process may be driving the symptoms,” Soloski said.

Lyme test challenges

Scientists haven’t yet come up with a way to confirm that the Lyme bacteria have been completely banished, because of certain peculiarities of this nasty bug, Soloski said. It doesn’t spend much time in the blood, moving quickly into tissue, and it doesn’t grow well in a culture, which is how most bacterial infections are confirmed.

For Kim Lewis, “the question of lingering bacteria is still very much an open one.”

“My team is looking for better compounds to treat Lyme, with an eye towards doing something potentially simple — finding a better drug to treat the acute disease, which might prevent PTLDS,” said Lewis, director of the Antimicrobial Discovery Center and a University Distinguished Professor at Northeastern University, who was not involved in the new study.

The hope, also, is that the right compound might eradicate any lingering bacteria in people with PTLDS, Lewis said.

As for the new study, it leaves open the question of whether there are still bacteria in the joints of patients with Lyme arthritis, Lewis said. “The authors think that the peptidoglycan remains in synovial fluid after the pathogen is gone. My guess is that the pathogen remains in the joints and sheds the antigen. It would be good to know how things really are.”

When it comes to finding physical explanations for patient symptoms, it’s not necessary to determine whether PTLDS is caused by lingering bacteria or to a malfunctioning immune system, said Dr. Peter Novak, an assistant professor of neurology at Harvard Medical School and director of the autonomic laboratory at Brigham and Women’s Hospital. Novak, who also was not involved in the new study, and his colleagues have discovered patients end up with damage to their small nerves and also diminished blood flow to certain areas of the brain.

He suspects that damage is due to changes in the immune system that were kicked off by the Lyme infection and remain after the bacteria have been obliterated. As for patients who experience improvement when treated with long courses of antibiotics, Novak believes this is because many antibiotics also have an anti-inflammatory effect.

So, while others look for ways to test for the presence or absence of the bacteria, Novak’s strategy is to try to make patients feel better by treating their symptoms.

FOLLOW NBC HEALTH ON TWITTER & FACEBOOK