On October 10, 1996, Linda, her knee aching and grapefruit-sized, came to a rheumatologist’s office in Palo Alto. She had an appointment with Dr. Rhonda Elaine Lambert, one of the region’s best in the field. Dr. Lambert held an adjunct position on Stanford’s faculty and served as a consultant to multiple sports teams, college and professional. She knew joints and her specialty was rheumatology.
She ran a battery of tests on Linda.
Linda’s X-rays were normal. Her rheumatoid factor was negative. Her test for antinuclear antibodies, a sign of lupus, was negative.
“Her labs were unremarkable,” Dr. Lambert said. Except for one number. Linda had taken a test to measure sedimentation rate, which provides a broad-based measure of inflammation. Her score should’ve been under 20. It was 94. Inflammation off the charts. Then there was the most obvious test of all, the eyeball test, the clinical exam. Linda had a grapefruit knee. Her joints ached. Her toes had exploded.
Dr. Lambert hesitated on a diagnosis. Even to this day, autoimmunity remains one of the most challenging conditions in medicine to diagnose with precision.
The Johns Hopkins University School of Medicine divides the materials of the diagnosing of autoimmunity into three categories that collectively sound like types of evidence at a criminal trial. The evidence can be direct, indirect, or circumstantial.
Direct evidence involves being able to transmit and reproduce the condition from one human to another—to, in effect, replicate the autoimmune process.
There aren’t very many examples of this. The best involves a doctor in the 1950s who pursued a time-honored tradition in science: experimenting on himself. The doctor injected himself with the blood of a sufferer of idiopathic thrombocytopenic purpura, or ITP—a condition that causes excessive bruising and bleeding, leading to purplish spots or regions on everything from skin to tongue and lips. The condition is caused by a low level of platelets, which cause clotting, and the doctor and his colleagues surmised this was because the body’s own immune system was attacking the platelets.
Within hours of injecting himself with the patient’s blood, the doctor’s platelet count plummeted and he had to be hospitalized. The result was so specific that it showed that an antibody in the woman’s blood—an autoantibody—attacked a self-antigen. The condition was renamed thrombocytopenic purpura.
One reason such evidence is hard to come by is simply that you can’t introduce a foreign body into a human, including another person’s cells, without initiating an immune response. This is why organ transplantation is so challenging. Studying the mechanisms from human to human involves many complications.
So scientists pursued a second course, indirect evidence. This entails replicating a human condition in mice. This is doable with multiple sclerosis, where the immune system interferes with the central nervous system. It can be induced in mice by vaccinating the mice with an antigen that is much like the one that humans attack in themselves.
But direct and indirect evidence allow diagnosis of only a handful of the autoimmune disorders. This leads to the heavy use of circumstantial evidence, which can be unsatisfying for patients and doctors. It involves looking at family history, the high levels of antibodies associated with the condition, and several other factors, including the circumstances that lead to onset, including stress.
There’s another big factor: Is the sufferer a woman?
“Females make more of an immune system response than males do. We all know that,” I was told by Dr. Hahn, the physician who treated rheumatology patients with gold shots in the late 1960s. Dr. Hahn rose to become the president of the American College of Rheumatology in the late 1990s, another glass-ceiling breaker in the field, and she is now chief of the division of rheumatology at the UCLA School of Medicine.
Women live longer, and they tend to be the last to die in, say, a famine or in an epidemic. The exact reasons aren’t known, but Dr. Hahn offers some theories as to why, in an evolutionary sense, women might have a stronger immune system. One possibility is that women confer the first immunity to their babies. Indeed, as she says, “the baby’s protection from disease is pretty much exclusively from the mother’s immune system antibodies.”
Another theory, she offers, “is that women tend to be caregivers.” Women, by definition, are there when the baby is born, whereas the man might’ve flown the coop. A caregiver might need higher protection from disease. Women generally have more body fat than men, so perhaps they have more immune system cells, Dr. Hahn postulated to me.
She also noted that many of the genes that are associated with lupus and rheumatoid arthritis are on the X chromosome. (Women have two X chromosomes, whereas men have one X and one Y.) So the math of autoimmunity became greatly weighted toward females. (Another piece of science trivia: When researchers want to create an antibody to study, they use a female animal, not a male. You get more antibodies.)
A woman’s relatively elevated immune system “is associated with living longer. But you have higher antibodies. That might make you sick and cause you to die,” Dr. Hahn said. What an incredible trade-off: longer life thanks to powerful defenses that can turn on themselves! This is an extraordinary insight too into the larger balance struck by our elegant defense. When the system contributes to longer life, it comes with a powerful potential cost. More defense, more risk. In day-to-day terms, the downside of a strong immune system, then, is that it can become more susceptible to being inflamed or set off by lack of sleep or stress or—this will likely go without saying—genetics. Fifty percent or more of cases appear to have a distinct genetic link, with a family member having had the condition, or a related one.
Another factor that can throw the immune system out of whack is infection. Say, for instance, a pathogen invades the body. The immune system then responds and succeeds in eliminating the pathogen. But this response can spur autoimmunity when the immune system doesn’t fully shut down and remains in hyperdrive, even though the pathogen has been ousted from the Festival of Life.
These are the same kinds of mechanics, incidentally, that make smoking such a risk for rheumatoid arthritis. Smoking introduces all sorts of foreign particles into the body, sucked down the throat and into the lungs, turning the immune system into a busybody surveying the particles and damage. In the case of rheumatoid arthritis, a possible cause is smoking—“an enormous possible trigger,” explained Dr. Lambert, Linda’s doctor.
Linda’s case didn’t offer Dr. Lambert much in the way of direct or indirect evidence. The circumstantial evidence spoke volumes. She wasn’t a smoker, but she had a host of other risk factors.
Inflammation. Check.
Infection. Check. Prior to onset of arthritis, she’d had strep—a disease that might’ve set her immune system off and running.
Sleeplessness, Check.
Stress. And then some.
Linda had first seen Dr. Lambert on October 10. She returned two weeks later. This time, Dr. Lambert took virtually one look at her and just knew.
Linda had to be moved into the clinic in a wheelchair. Multiple joints were now inflamed. “Her disease had taken off like a rocket,” Dr. Lambert said.
At this point Dr. Lambert was sure Linda was suffering from rheumatoid arthritis. The doctor prescribed a first-line treatment of steroids. Specifically, she gave Linda a drug called prednisone. Dr. Lambert described it as “being like a big hammer. It shuts a lot of things down.”
It’s used to treat many inflammatory diseases. “But unfortunately it has all this spin-off all over the body.” Such as weakening your immune system, leaving you susceptible to infection, and making it even harder to sleep. That’s partly because it interacts with the adrenal gland.
“We really don’t like to use prednisone in the long term.”
Dr. Lambert felt she had no choice in Linda’s case because the damage to Linda’s joints had progressed so quickly and was so extreme that it could have become irreversible. “She likely would have ended up in a wheelchair permanently.”
The steroids put Linda out of balance. She couldn’t sleep at night, so she took Ambien and then a drug called Flexeril, a muscle relaxant, to stay asleep. That was the bad news.
The worse news is that the steroid regimen wasn’t working—not well enough.
Her hands hurt so much, she couldn’t button her pants. She started wearing pull-on pants. One day, when she dropped her daughter off at school, another little girl came up to her and in all innocence asked, “How come you always wear the same clothes?”
Linda couldn’t use her hands to pick up her infant son and would try to grasp him with her forearms. She wore gloves when she went out in case she had to shake hands with someone, to soften the impact.
When Linda came back in December 1996, Dr. Lambert drained 65 cubic centimeters of fluid from her left knee (about 65 teaspoons) and 30 cubic centimeters from her right knee. She was on 30 milligrams of prednisone, and the tablets are available only in 20 milligrams.
By now Linda was also taking a drug called methotrexate, which was originally used in chemotherapy for blood cancers, aimed at interfering with malignant white blood cells. But white blood cells are immune system cells, so when they are attacked, the body becomes highly vulnerable to infection.
“I had an eye infection, an ear infection, a yeast infection, a bronchial infection—in every orifice or opening you could get an infection, I had one. I was a petri dish. I was kind of thinking that the swelling was better than this.”
By the spring of 1997, Linda was on fifteen medications—some to help with the autoimmunity, some to stem the activity of the other medications.
Then, as things were seemingly close to being under control, another trauma hit.
Linda had gotten enormous help from her mother-in-law throughout the prior six months. That April, her mother-in-law committed suicide. A lifeline was gone, and Linda’s marriage began to deteriorate. It’s not an exaggeration to say that as Linda’s immune system lost balance, her life fell out of balance too.
As the drugs began to take effect, lessening the rheumatic symptoms, her immune system continued to wrestle with basic challenges. In late summer of 1997, a major client wanted her to come to London. The anti-inflammatory medications had weakened her immune system to the point that she was suffering from a terrible cough. In London, she went one night to see a play called Art. She took a pillow with her to the theater to cough into.
One day she met with her client’s European president. She was supposed to be advising him, but all she could do was cough. She excused herself. In the hallway, she tried to gain control. But for twenty minutes she coughed. “I couldn’t go back in the room.”
Linda was making excruciating trade-offs with her immune system, suppressing it at great cost. But medicine was on the verge of snagging this problem by the tail.