Why Doctors Misdiagnose Autoimmune Diseases

Even specialists often struggle to make sense of the puzzling symptoms that come with these slow-moving disorders

A close up of a woman’s arms and hands with vitiligo.
Photo: MarijaRadovic/E+/Getty

TThe patient came to her doctor with a low-grade fever, some achiness and fatigue, and a touch of diarrhea. The doctor told her it was probably a mild case of the flu. But weeks later the symptoms hadn’t gone away. The doctor ran some lab tests, but the results didn’t clearly indicate any problems, and he insisted there didn’t seem to be anything physically wrong with her. Still feeling off, she eventually saw other doctors. Yet over years of continuing and even slowly worsening symptoms, none of these doctors were able to tell her what was wrong. Finally, 15 years after she first felt ill, a specialist gave her the diagnosis: She had lupus erythematosus, the most common form of lupus — an autoimmune disease, where the immune system drives the disease instead of protecting against it.

If only that story were unusual. While 1.5 million Americans have been diagnosed with lupus erythematosus, experts believe the number of undiagnosed cases is higher. And lupus is just one of more than 100 autoimmune diseases affecting nearly 25 million Americans, diseases that together present a challenging and often frustrating path to diagnosis for doctors and patients alike. “These patients often get sent on a long journey before they get an answer,” says Robert Lahita, M.D., the chairman of medicine at St. Joseph’s Healthcare in Wayne, N.J., and the autoimmune specialist who finally diagnosed that lupus patient. “Some physicians will tell them it’s all in their head. It’s not, and they can be miserable for years until they get diagnosed.”

AAutoimmune diseases take hold when the immune system — for reasons that still aren’t understood — start to mistake normal cells and tissue for a threat, and attack them as they would an invading infection. Some of the more common examples include rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease, in which the immune system attacks, respectively, the joints, the outside of nerves, and the intestinal lining or any part of the gastrointestinal tract.

Many autoimmune diseases can be debilitating, and can even lead to an early death. But it can take years and even decades for the full, unmistakable symptoms, damage, and abnormal test results associated with a specific disorder to develop — for example, the ulcers that can form in the GI tract from inflammatory bowel disease, or the skin sores from some types of lupus.

Until then, the disease can smolder and slowly build, typically spawning symptoms that are vague, subtle, irregular, and otherwise hard to pin down, making diagnosis difficult or even impossible. “What plagues patients with these diseases is that it can take doctors a while to make sense of them,” says Anca Askanase, M.D., director of the Columbia University Lupus Center.

AAmong the typical symptoms in these earlier, less-acute stages are fatigue, aches, rashes, swelling, difficulty concentrating, and slight fevers. That’s not much help to doctors in narrowing things down, because any autoimmune disease — and indeed, a wide range of other common conditions — can cause any or all of these symptoms. But there are exacerbating factors that should cause doctors to want to consider an autoimmune disorder as a possible culprit. “If the symptoms persist for many weeks, if the appetite goes, if rather than just feeling tired you feel sick, and if there are no apparent other reasons for all this, then it’s time to wonder if something is going on,” says David Pisetsky, M.D., an immunologist at Duke University.

That potentially long delay before a doctor can put a name and cause on a set of vexing symptoms may end up feeling to the patient like a bigger problem than the symptoms themselves.

As an early step toward a possible autoimmune diagnosis, a primary-care physician with a patient facing these symptoms would typically order an “antinuclear antibody panel” or ANA, a blood test designed to detect some of the distinctive proteins an errant immune system can enlist to target the healthy cells it’s attacking. Negative results would usually rule out autoimmune problems, at least for the time being, while a strongly positive result generally calls for a visit to an immunologist. Unfortunately, it’s often not that simple, because ANAs frequently come back slightly positive, offering little guidance. “Doctors have to interpret a weakly positive result with caution,” says Neilanjan Nandi, M.D., who heads the Center for Inflammatory Bowel Disease at Drexel University. “It doesn’t really have a lot of clinical significance.”

For a specialist trying to tease out an answer, or primary-care physician who’s trying to decide if a specialist is needed, other considerations may be weighed. These include a family history of autoimmune problems, because susceptibility can be passed along through genes. Infections, physical or mental stress, poor nutrition, and exposure to pollutants or other harmful chemicals may also raise suspicion, not because they’re thought to be causes of autoimmune diseases, but because they may serve as potential triggers for a disease that might otherwise have been quietly lying dormant.

If the patient is a woman, African American, or in a more vulnerable socioeconomic status, then that, too, may move the needle toward an autoimmune diagnosis, because rates of the disorders are substantially higher in those populations. An African American woman on average has about a 100 times greater chance of ending up with lupus as a male of European ancestry.

ItIt may take multiple visits to the same or different doctors over months and years, often repeating the same questions, and undergoing the same physical exams and tests, before the answers start to add up. “It’s detective work,” says Askanase. “You won’t see everything the first time you look at the scene of the crime, but you keep revisiting it in the hopes that you’ll notice something new.”

That potentially long delay before a doctor can put a name and cause on a set of vexing symptoms may end up feeling to the patient like a bigger problem than the symptoms themselves. “The emotional toll these diseases can take if they’re not diagnosed and treated can be life-changing,” says Nandi. “They can lead to anxiety and depression, put you out of work, and disrupt healthy relationships.”

The lack of a diagnosis can also keep helpful treatments out of reach. There are a number of new drugs that are targeted to specific autoimmune diseases, and that are highly effective for many patients in keeping their disease under control. For example, the drug Xeljanz has worked well for some patients with rheumatoid arthritis, and was approved last year for ulcerative colitis, a common form of irritable bowel disease. Other new autoimmune drugs are “biologics” — drugs made from the components of living cells and tissue, often allowing them to work more compatibly with the body’s natural mechanisms. But doctors are unlikely to prescribe these sort of high-powered new drugs without a firm diagnosis, because insurance may not cover the potentially multi-thousand-dollar costs, and there’s a greater risk of the drug not working or causing side effects.

For patients who are suffering with the symptoms of what seems like an autoimmune disease, but who don’t yet have a clear diagnosis and targeted treatment, doctors typically rely on steroids like Prednisone to provide some relief. These drugs are effective on most of the typical symptoms of autoimmune disease — but they take a toll. “Compared to targeted therapies, steroids are a barbaric treatment,” says Nandi. “They shut down the immune system so it can’t attack, but they carry serious side effects.” Among them: bone loss, swelling from water retention, disfiguring lumps on the neck, poor wound healing, joint deterioration, and a reduced ability to fight off infections. In addition, steroids don’t help about a fifth of patients with autoimmune problems.

DDoctors’ inability to firmly diagnose a patient’s specific autoimmune disorder frequently leaves the patient feeling let down by their physicians and the health care system. That’s only natural, says Askanase. But establishing a trusting relationship with a doctor is important to a good outcome, she adds. “You want to find a doctor who understands the process of getting to a diagnosis, and feel like you’re in a partnership with that doctor,” she explains. While repeatedly switching doctors simply because a firm answer isn’t forthcoming can cause more problems than it solves, she says, patients certainly ought to expect their doctor to make it clear they’re holding up their side of the partnership. “If you don’t think your doctor is listening to you and paying attention to what’s going on with you, it’s okay to invite another physician into the conversation,” she says. “You have a right to be heard by your doctor.”

Part of being heard when symptoms suggestive of an autoimmune problem persist is to get in front of a doctor who specializes in autoimmune diseases — an immunologist, or in many cases a gastroenterologist, hematologist, or endocrinologist, depending on the symptoms, patient history, and lab results. That’s because even the most caring, competent, primary-care physicians aren’t well-equipped for the detective work needed to pin down an elusive autoimmune disorder. “The average primary-care physician sees one new rheumatoid arthritis patient every two years,” notes Pisetsky. “That doesn’t allow going down the learning curve fast enough to be good at recognizing it.” If a primary-care physician keeps balking at providing a referral to a specialist, the patient may need to simply find one on their own — most specialists will try to help patients who reach out directly.

Perhaps most upsetting to patients living with challenging, autoimmune-like symptoms and no diagnosis is feeling that doctors are telling them that nothing is wrong. Virtually all experts agree that’s an inappropriate message for a doctor to send to a patient who’s feeling sick and worried. But some doctors send it anyway. “I’ve seen patients who were told to see a psychiatrist and get medications before they eventually got a proper diagnosis,” says Lahita.

On the other hand, advises Askanase, patients should take care not to confuse a doctor’s inability to produce a diagnosis and hesitation to prescribe a drug with the doctor not believing the patient is suffering with what may well be an autoimmune disorder. “I don’t think most doctors think in terms of ‘this is all in your head,’” she says. “It’s more that they’re trying to say, ‘I just don’t see it yet.’” That’s why they may suggest lifestyle changes such as meditation, better diet, and an exercise program, she adds — not because they’re trying to dismiss the patient’s concerns or blame the symptoms on patients’ own habits and behaviors, but because these changes actually do often provide some relief from autoimmune symptoms until a specific diagnosis emerges and opens the door to targeted treatments.

Still, patience can be easier to prescribe than it is to accept as a treatment. “I get that, I really do,” says Askanase. “We doctors know we need to figure out how to diagnose these diseases earlier on.”

David is a Boston-based science writer. The most recent of his five books is WRONG, about the problems with medical research and other expertise.

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