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While lugging a mattress up the stairs, Matt Smith lost his grip, fell on a post and broke two ribs. The pain afterward was so intense that when he got in or out of the car, he bit down on wooden sticks. Extra-strength acetaminophen, also known as Tylenol, helped. But a few weeks later, the organic farmer from Wisconsin uncharacteristically lost his appetite. At a local clinic, a doctor ordered blood tests.
Later that day, as Smith was delivering spinach to a market, the doctor called. Smith's liver function levels were dangerously high, the doctor said, and he needed to go straight to the emergency room.
A liver biopsy suggested a drug-induced injury, and too much acetaminophen can damage the liver. Doctors treated Smith for acetaminophen toxicity, even though he took no more than four 500-mg pills a day, which is considered safe.
But soon, he developed joint pain, swelling, hives, an occasional fever and alarming tissue changes in his lungs, which clouded his medical outlook. To the surprise of Smith and his doctors, it was another physical peculiarity that months later provided the clue to his diagnosis with a rare disorder he had never heard of before.
The discovery eventually led to treatments that cleared up his condition, even though they made it harder for him to recover later from covid-19.
Getting the diagnosis "was very critical to getting the ball rolling," he said. "It sent me in the right direction."
• Liver emergency
Smith, now 72, was mostly healthy before late 2020, though sometimes his heartbeat suddenly raced. In November of that year, on Election Day, he underwent an ablation procedure that creates tiny scars in the heart to correct faulty signals.
After the procedure, his heartbeat normalized. But eight days later, as he was hauling the new, rolled-up mattress up the stairs, the king-size bed slipped and crushed Smith into the newel post.
An X-ray showed two broken ribs, and Smith started taking acetaminophen, staying well below the maximum daily dose of six extra-strength pills, or 3,000 milligrams, per day. But by early December, Smith, a food lover, suddenly felt tired and sick to his stomach. "There was no desire to eat," he said. "The sensation of food was gone."
Levels of two liver proteins involved in metabolism were 30 times and 47 times higher than normal, his blood tests showed. Smith and his wife, Susan, were bringing spinach to a makeshift, contact-free market set up during the height of the pandemic when the doctor called. As a snowstorm set in, Susan dropped Smith off at the ER, not allowed to join him because of covid-19 restrictions.
In the hospital, doctors gave Smith an antidote for what they assumed was acetaminophen poisoning, even though he apparently hadn't overdosed. Tests showed his liver problems didn't stem from cancer, a virus or alcohol use. Doctors started Smith on prednisone, a steroid that reduces inflammation and tamps down the immune system, and his liver levels returned to normal. That suggested he had some kind of autoimmune disease, when the body mistakenly attacks its own healthy tissue, but doctors weren't sure exactly what was going on.
The soonest he could see a rheumatologist, a doctor who specializes in autoimmune disorders, was four months later, in March 2021. As he waited for an explanation of his baffling illness, Smith started to exhibit new symptoms. His hands and feet became swollen and achy. During cold weather, the tips of his fingers turned blue. He periodically had itchy hives on his chest and a slight fever. His muscles felt weak, especially in the shoulders.
The rheumatologist told Smith that he seemed to have inflammatory arthritis, or joint inflammation, and autoimmune hepatitis, or liver inflammation, both triggered by an overactive immune system. The doctor speculated that the conditions might be manifestations of a rare, systemic autoimmune disorder, such as Still's disease or something known as RS3PE, both of which involve swollen joints.
But the doctor was stumped by the unusually high liver function tests, or LFTs, that had shown up during Smith's exam in December 2020. "I cannot explain his elevated LFTs … on the basis of any discrete rheumatological process," the rheumatologist wrote in a summary of his visit with Smith.
Regardless of the exact cause, the doctor decided that the treatment would remain the same: prednisone, with the goal of tapering the dose to avoid serious side effects of the drug's long-term use, such as thinning of the bones, high blood sugar and increased risk of infections.
The doctor also prescribed hydroxychloroquine, an immunosuppressant often used to treat malaria, but Smith broke out in an allergic rash from it and stopped taking it after two weeks.
• Second opinion
Smith and Susan, wanting a clearer diagnosis, decided to get a second opinion. They went to Mayo Clinic in Rochester, Minnesota, where several doctors evaluated Smith during two multiday visits in June and July 2021.
By then, Smith recalls, an increasing source of his discomfort was his hands, which had become enlarged and misshapen. "They were swollen, red and funky," he said. "They were sausage fingers."
Kristen Hanzel, an internist at Mayo who conducted his initial exam, remembers Smith's hands. "They looked thickened," she said. "The skin didn't look quite right."
The next day, Smith saw Kerry Wright, a Mayo rheumatologist who specializes in inflammatory arthritis. She also assessed his hands, bringing them to her face for a close look. "You have mechanic's hands," she told him.
Smith started talking about the farm equipment he operated. But Wright said no, not that; she was referring to a symptom of a rare autoimmune disease.
She suspected the thick, cracking skin of his swollen hands was a sign of antisynthetase syndrome, which can cause inflammation in several parts of the body. For unknown reasons, people with the condition develop antibodies that attack enzymes called tRNA synthetases, which are crucial to the body functioning properly.
The syndrome usually involves joint pain and swelling, muscle pain and weakness, and unexplained fever. Hallmarks also include rough-skinned "mechanic's hands" and Raynaud's phenomenon, in which cold temperatures turn fingertips blue, along with interstitial lung disease, or potentially life-threatening damage to tissue between small air sacs in the lungs.
At the time, Smith didn't have much trouble breathing, the typical indicator of the lung problem, but CT scans found worrisome changes in his lung tissue. One of his friends had died of the lung condition two years earlier, at age 74.
"It was scary" to think he might be developing the same problem, Smith said.
Antisynthetase syndrome normally doesn't include the liver irregularities Smith had experienced. But Wright said muscle inflammation that is characteristic of the syndrome can increase liver enzyme levels in the blood. That, along with the acetaminophen and a cholesterol-lowering drug Smith was on - perhaps in addition to a separate, unidentified liver condition - probably accounted for his sky-high liver enzyme levels in late 2020, Wright said.
To confirm her suspicion of antisynthetase syndrome, Wright ordered blood tests for antibodies associated with it. Smith was negative for the most common one, Jo-1, but he was positive for two others, including one called PL-12. That made Wright certain Smith had the syndrome.
"The antibodies help us to be more confident about the diagnosis," she said.
Nationwide, fewer than 50,000 people have antisynthetase syndrome, according to the Cleveland Clinic. Wright said she encounters patients with it a few times a year. For Hanzel, the Mayo internist, Smith was the first patient known to have the condition during her 22 years in medicine.
• Tailored treatments
With that diagnosis in June 2021, Smith soon started taking rituximab, a periodic infusion used to treat some autoimmune disorders and blood cancers. He hoped he'd start feeling better soon.
But in September 2021, shortly after his first rituximab treatment, he was hospitalized for difficulty breathing and low oxygen levels in his blood, signs that his interstitial lung disease might be progressing.
The next month, in another apparent display of his antisynthetase syndrome, a rash popped up on his chest, arms and face. It itched, blistered and caused his skin to flake off, as if he had been sunburned. "It was my scary Halloween face," Smith recalls.
Shortly afterward, Smith started taking a daily immunosuppressant pill, mycophenolate, that is taken by some organ transplant recipients. That, the rituximab and the prednisone he was still on largely prevented flare-ups in 2022 and 2023. By January 2024, after his last of 10 rituximab infusions, a scan showed his interstitial lung disease was gone. After more than three years, it seemed like his therapeutic odyssey was over.
But the next month, he contracted covid-19 and pneumonia, for which he was hospitalized twice, requiring oxygen therapy and intensive care. He couldn't seem to get over the infection. Even after a few months, in June 2024, he was struggling to breathe. His treatments for antisynthetase syndrome, especially the rituximab, probably made it hard for his body to clear the coronavirus, because they suppress the immune system, doctors said.
Susan, a science writer, blames herself for her husband's backslide, saying she caught covid-19, probably while watching basketball superstar Caitlin Clark play at the University of Iowa, and unwittingly brought it home.
At the beginning of 2024, "we got this great news," she said. "He's all better. And then I gave him covid."
Eventually, a 10-day course of the antiviral drugs Paxlovid and remdesivir helped Smith bounce back from covid.
Today, mostly retired from farming, Smith is back to gardening, going to the gym and riding his e-bike near the family's farm west of Madison, around a hilly landscape known as the Driftless Area.
His hands occasionally tingle, and his fingertips sometimes still turn blue. But his joint pain and rashes are gone, and he feels stronger. He stopped taking prednisone early this year, and his new rheumatologist said his antisynthetase syndrome is in remission. How long that will last, doctors can't say. If needed, the new doctor said, she'll start him on rituximab again.
Smith and his wife are glad they pursued a second opinion to better understand what was ailing him. Medicare and his supplemental insurance covered the Mayo visits, except for one test, and the Mayo doctors shared information with their regular doctors, they said.
Without the diagnosis, "I don't think he would have been on those medicines" to help him recover, said Hanzel, the Mayo internist. "These are a little bit more heavy-duty."
"Some people worry about hurting their doctors' feelings," Susan said. "But most insurance pays for a second opinion. If [your regular doctors] don't know what you have, people should take advantage of that." If they hadn't pressed for more information, "the outlook would have been a lot bleaker," Smith said. "I'm really lucky. I'm feeling blessed."