An Elegant Defense

by Matt Richtel

  In 1975, Carolyn Wiener, a behavioral scientist at the University of California at San Francisco, wrote a research paper that captures the reality of living with autoimmunity. The article is painful to read. It gives shape to the emotional side of living with a disease, rheumatoid arthritis, that is difficult to diagnose, with “no cure available.”

  The paper starts with a journal entry from a twenty-nine-year-old woman suffering from RA:

  Being physically comfortable

  And doing a simple chore

  Can raise one’s spirits to

  Levels of supreme joy.

  Persistent pain and wretched

  Tiredness brings one to

  Near despair

  In the next forty years, I

  Wonder how many variations thereof

  I shall experience.

  “Rheumatoid arthritis patients learn, along with their diagnosis, that the disease is not only incurable but that its specific manifestations are unpredictable. As often as not, they hear the physician say, ‘You are going to have to learn to live with it,’” the paper reads.

  Among the “self-doctoring” strategies that the paper describes for coping are “ingestion of celery juice, or massive doses of vitamin E or plastic bags filled with powered sulphur wrapped around the feet at night . . . a poultice of ginger root steeped in vodka and an alloy.”

  Another tactic in the paper is referred to as “covering up.” Autoimmune sufferers would pretend they weren’t suffering, try to look as if nothing were wrong. It was a mixed blessing. Friends and family would then assume nothing was wrong and expect full activity from the afflicted.

  I was privileged to hear the intimate medical and personal narratives of two autoimmune sufferers, Linda and Merredith—two of the stories I share in this book. Their stories also provide insight into some of the key factors that impact the balance of everyone’s immune system—namely, sleep, stress, hygiene, family history, and the ecosystem of our gut, known as the microbiome.

  And they tell us about the fight of this ever-increasing group of patients to move out from the shadows.

  29

  Invisible Evidence

  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. B
ut 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.

  30

  Best of Both Worlds (Sort Of)

  In November 1998, the U.S. Food and Drug Administration approved one of most anticipated drugs in medical history: Enbrel. It was aimed at treating rheumatoid arthritis.

  What was so widely anticipated about Enbrel, made by a Seattle company called the Immunex Corporation, was that it was designed specifically to limit the effects of an overreactive immune system without undermining the entirety of the system.

  It was built around the discovery of monoclonal antibodies in the seventies. The ability to isolate and replicate individual antibodies was allowing drugmakers to develop medicines constructed around very specific molecules. These antibodies, injected into the body, would theoretically attach to and react with only very specific cells in the body.

  For instance, Enbrel works by using monoclonal antibodies to interact with a particular cytokine—an immune system signaler—known as tumor necrosis factor, or TNF. What TNF does is send a signal that causes a cell to die, specifically by experiencing apoptosis. This is a crucial normal process in our Festival of Life, and it is quite elegant and orderly. A cell receives a signal to die, essentially to kill itself, and it begins to break into little digestible chunks that then get eaten by the janitors, the macrophages. (Apoptosis comes from a Greek word meaning a falling off.)

  With Enbrel and other drugs that act on TNF, the idea is to get the cells that are causing problems to commit suicide. Obviously, getting malignant cells to off themselves can be useful in cancer. In the case of rheumatoid arthritis, it’s also advantageous to have overzealous immune cells commit apoptosis. Instead of attacking Linda’s body, the cells would kill themselves.

  (Heady stuff, and even weirder given another bit of trivia: The monoclonal antibody used in Enbrel is produced in hamster ovaries.)

  Dr. Lambert couldn’t wait for Enbrel to come out. “It was a game changer. We all knew that. We were waiting for it.”

  In early 1999, Linda took her first infusion of Enbrel via a shot in her upper thigh. It took several months to work, and then . . . whoa.

  The swelling began to subside. The pain began to diminish.

  Enbrel wasn’t scorching the earth of Linda’s immune system, as steroids could do, but acting in a more targeted fashion. This was part of the dream of immunology, going back to Jacques Miller—to understand the immune system well enough to tinker with it.

  “My immune system is allowed to work, and this binds to the parts of my immune system that are attacking me and neutralizes them,” Linda said, sounding awed. “Once I went on this drug, my life just changed.”

  Enbrel is now one of the bestselling drugs in the entire world. It generated $5.5 billion in sales in the 2017 fiscal year for Amgen, the company marketing it.

  The story of how these drugs work is even more sensational when it comes to cancer, and I’ll tell you that story shortly.

  But this is not pure miracle. Autoimmunity is too complex for one size fits all, and the new drugs still le
ave many people feeling invisible.

  This brings us to Merredith Branscombe—both an echo of Linda and a study in contrasts.

  31

  Merredith

  Merredith, born just two years after Linda and nine hundred miles away in Denver, woke up one morning in 1977 with a low-grade fever. Her joints hurt. It felt like a vise was crushing them. Merredith began to experience mysterious symptoms intensely through her teens—a low-level surfacing of aches, pains, and fevers largely left untreated. The doctors thought she might have mono.

  Merredith was in much the same boat as her mother, who would experience unusual spells, body pain, and swelling, and often had trouble digesting her food. Merredith remembers her mother with her hand held over her forehead, feeling faint. Was she ill? It was hard to pin down. Maybe it was her childhood, and the secret, and the stress of a life spent feeling like an outsider.

  Merredith’s family lived in a neighborhood called Park Hill. In the late 1960s, the area was white but integrating. Neighbors didn’t like that. On multiple occasions, Merredith’s family came home to find flyers posted on their house urging them to leave before the colored folks arrived.

  Merredith Branscombe. (Courtesy of Merredith Branscombe)

  Merredith’s parents disagreed with this bigotry. Her father, an editor at The Denver Post, did some research showing that property values actually went up, not down, when neighborhoods integrated. There was more demand for homes. Merredith’s father wrote the first editorial in the paper urging integration. The next night, a Molotov cocktail was thrown through their window. It was as if the white people in the neighborhood were overreacting to the presence of something they perceived as other. What was alien? What was self? The country wrestled with itself and integrated.

  It was all very personal to Merredith’s mother, Bea. She had been raised Catholic, then Congregational; she had married an Episcopalian and worked with black and white churches to foster integration. She also worked in the civil rights division of the Colorado state government. She’d learned the hard way to fight for integration.