Never give up

Severe anemia sometimes left her too weak to speak. A rash covered much of her body. She rarely ventured out of her home in Menlo Park, California, except for doctors’ visits and a weekly bridge lesson.

Though her thinking was foggy, she resolved to find answers to her mysterious condition, and she spent rare, lucid moments scouring the medical literature and preparing questions for a succession of specialists who were unable to offer answers or relief.

“Anger is a powerful motivator,” she said. “I became irritated with my clinicians whom I felt were unable to help me but were letting me wither. If they were not going to help me, I would have to help myself. My focus became trying to get answers for what was wrong with me.”

Shefrin’s illness would take her on a yearlong odyssey seeking an explanation for her bizarre set of symptoms. Her persistence, as well as a stroke of serendipity, eventually led her to a pair of experts at Stanford.

It began in the fall of 2016 as Shefrin celebrated a highlight of her career, when she was named a distinguished alumna of the School of Dental Hygiene at the University of Manitoba in Winnipeg, Canada. At a gala dinner in her honor, a sea of health care practitioners gathered to acknowledge her contributions to the profession as clinician, educator and clinical researcher.

It had been a stressful visit, but on the flight home, Shefrin began to relax and took a brief nap, only to be awakened by a sudden pain in her left hip, which felt like it was on fire.

“I had never experienced such intense bone pain in my life. I was in agony,” she recalled. “Almost instantly, I went from healthy, though under a lot of stress, to being incapacitated.”

The pain persisted, and a week later she broke out in a rash of splotchy, red welts that covered her from neck to toe and became a persistent irritant.

In a matter of months, Shefrin, a once-vibrant and creative woman, became bed-bound, mentally confused and tortured by pain, amid dramatic changes in her immune system. She refused to see friends — she didn’t have the energy — and became increasingly dependent on her husband.

“I was always in bed. I had accomplished so much in my life. Yet here I was, trapped in bed. I couldn’t think. I could barely talk,” she said.

Shefrin, 68, is soft-spoken and slender, with silvery gray curls and an artistic flair: She designs and makes most of her distinctive clothes, some of which are sold in local boutiques. After her years in dental hygiene, she managed clinical trials at Syntex Corp., contributing to FDA approval of two major painkillers — Aleve and Toradol — and wrote extensively on the ethical and regulatory aspects of clinical investigations.

After her return from Canada, she contacted her primary care doctor at a community clinic, who ordered a series of blood tests. These indicated several abnormalities, including a very high platelet count — cells that help form clots and minimize or prevent bleeding. A normal platelet count can range from 150,000 to 400,000 cells per microliter of blood. She had at least twice that number.

“I was really scared,” she said.

She was referred to a hematologist, who found that she also carried a mutation in a gene known as JAK2, or Janus kinase 2. Together with the high platelet count, the finding persuaded the hematologist that Shefrin had a form of blood cancer known as essential thrombocythemia, which can cause clotting and bleeding problems. It seemed logical, given that about half of ET patients exhibit the JAK2 mutation.

But the diagnosis did not explain her rash, bone pain or low hemoglobin, a component of red blood cells, which eventually turned into severe, chronic anemia. It also didn’t account for some other abnormal blood results, including an unexplained finding of monoclonal gammopathy, a condition in which white blood cells run amok, producing a single antibody over and over again, sometimes as a prelude to cancer.

Nonetheless, the ET diagnosis prevailed during most of her illness, though Shefrin was never convinced it was accurate.

A constant support

Adding to her health concerns, on the same day in January 2017 — a Friday the 13th — that she was diagnosed with the blood disease, her gynecologist delivered another blow: She had a malignant tumor in one of her breasts.

“It was awful, one of the worst days of my life,” Shefrin said.

Her husband of 48 years, Hersh Shefrin, took time from his job as a finance professor at Santa Clara University to care for her. He ran the house, shopped for groceries, and cooked for his wife (who had studied at the famed Cordon Bleu culinary school in London), trying to prepare meals that would appeal to her meager appetite. A “born nurturer,” he was her constant support, attending all medical appointments and taking copious notes while trying to maintain an upbeat outlook in the face of tremendous challenges, she said.

“My job was to make sure she knew there was light at the end of the tunnel and to relieve as much stress as possible so she could focus on healing,” said her husband, who is a pioneer in behavioral economics. “I am a decision theorist and economist. I know from my research that if you are optimistic, you cope better. My being up could help her be up.”

He was on call 24/7 and rarely slept through the night, as Shefrin’s symptoms were most intense at that time. He called them “nights of pain, interrupted by sleep.” She took Tylenol and sometimes low doses of oxycodone, but knew from her research to be wary of the opioid’s addictive potential. Her husband prepared middle-of-the-night snacks — pasta, cabbage salad or fruit — to keep up her energy. And he seized on the positive: “It will get better,” he told her. “You may not see the light yet, but it’s there.”

During the day, she often fell into an exhausted sleep, while her husband retreated to his home office to work, priming himself with coffee to stay awake and keeping one ear open for a cry for help.

“If I didn’t have a husband who cared, as he did, I would have said, ‘What is the point?’ I was in so much pain. … He was counting on me to get better,” she said.

He proposed little diversions to counter her misery. “I dreaded the weekly blood draws,” she recalled. “He’d say, ‘Let’s go and get it out of the way, and then we’ll go for a short walk afterwards.’”

After Shefrin’s breast cancer diagnosis, she needed surgery to remove the tumor. That had to be delayed a couple of times because she didn’t respond well to chemotherapy to bring down her platelet count, a measure taken to avoid the serious risk of a blood vessel blockage or a bleeding problem during the operation.

The surgery finally happened in April 2017 and was followed by six weeks of radiation therapy. But she hit a new low just after her final treatment, when symptoms of what she thought was a urinary tract infection worsened. “I lay down on the bed, and I said, ‘Hersh, call the doctor. I think I’m dying.’ … I can’t remember ever being so sick. I was confused, I had severe vertigo, and I couldn’t sit up.”

That’s when she first went to Stanford Hospital, where she was treated for dangerously low sodium levels, thought to be associated with treatment for the urinary tract infection. Clinicians there investigated many possible reasons for her condition, including metastatic bone cancer.

The weeklong stay proved to be a turning point when she met Bernice Kwong, MD, a clinical associate professor of dermatology. Kwong was called in to help treat Shefrin’s rash and ultimately became instrumental in piecing together the puzzle of Shefrin’s disease.

While in the hospital, Shefrin was encouraged to follow up with a Stanford hematologist. But she hesitated, having already seen four hematologists elsewhere, none of whom could explain or effectively treat her condition.

“The clinicians would say, ‘Our time for today is over. We’ll see you in six weeks.’ Then I would ask, ‘What’s the treatment plan?’” she said, her quiet voice rising in frustration. “Despite my polite and respectful questioning of my doctors, I never had a treatment plan that addressed all my symptoms.”

Trying to explain symptoms

Desperate for answers, she finally worked up the energy to make an appointment with Jason Gotlib, MD, a professor of medicine who specializes in bone marrow diseases in which patients overproduce certain kinds of blood cells. By then, it was late August and Shefrin was 11 months into her illness. Gotlib, a genial clinician with an easy manner, recalled Shefrin’s frustration when they first met.

“She was just completely handicapped” by her symptoms, he said, also recalling having doubts about her diagnosis. “My first impression was that her clinical presentation didn’t fit with ET.”

His skepticism rose when he saw that her lab findings showed extremely low hemoglobin, elevated white blood cells and 10 times the normal amount of C-reactive protein, a blood marker for increased inflammation and infection. Her erythrocyte sedimentation rate, a red blood cell test that also shows levels of inflammation, was off the charts, he said.

Gotlib said some of Shefrin’s symptoms, including the anemia, the inflammation and the higher-than-normal white count, could not be solely explained by ET. “I said to her, ‘You have the JAK2 mutation, which suggests ET, but something else is going on. And, by the way, what is this unusual rash?’”

That rash prompted Gotlib to refer Shefrin back to Kwong, who directs the Supportive Dermato-Oncology Program at the Stanford Cancer Center and with whom he often works on cases involving cancer patients with skin problems.

It was then that Shefrin sensed a positive shift. “Hersh and I left with so much hope because Dr. Gotlib said, ‘We’re going to get to the bottom of your illness. What you have is a puzzle, and I like to solve puzzles.’”

When Shefrin visited Kwong a few weeks later, the dermatologist immediately recognized her from her earlier hospital stay.

“She had the same rash, but this time, in addition to trying to treat the symptoms of the rash with medications, our interest shifted to trying to think about how this rash might help shed light on everything else that was going on with her health,” Kwong recalled. So late that evening, after she put her three children to bed and made their lunches for the next day, Kwong sat down at her computer in her Palo Alto home and reviewed everything in Shefrin’s lengthy medical record.

“Deep in her chart I noticed she had this monoclonal gammopathy that had been detected a year before and was thought to be of undetermined clinical significance. And I knew from our examination she had urticaria [rash]. At that moment, I knew I had to find out if she had arthritis or bone pain,” she recalled.

That connection harked back to a single moment in Kwong’s residency training at Stanford in 2009, when she was cramming for her dermatology boards. After clinic hours and between patients, her senior resident, Kerri Rieger, MD, PhD, now a clinical associate professor of pathology and of dermatology, would frequently give her pointers for memorizing thousands of facts, many of them very unusual, that might be relevant in her practice years later.

When they came to a rare disease known as Schnitzler syndrome, characterized by bone pain, a rash and monoclonal gammopathy, Kwong struggled to ingrain this trio of symptoms into her brain.

“Kerri told me she struggled too, but I am so grateful that she shared with me how she remembered the three symptoms. She taught me to picture a man by the name of Schnitzler, who had bone pain, urticaria and a monoclonal gammopathy. She drew me a picture of this man and gave me the mnemonic which allowed me to successfully memorize the associated findings,” Kwong said. “I remember thinking at the time, ‘Is this disease real? Is it ever going to matter that I remember these little details? Will I ever see this in my life?’”

Now it was real, and the details mattered intensely. She asked Shefrin to return the next day for a small piece of skin to be removed from her arm for evaluation.

The results showed that her skin was loaded with neutrophils, specialized white blood cells that are among the first responders to inflammation. Neutrophils frequently accompany a rash, Kwong said, but when combined with bone pain and monoclonal gammopathy, the cause can be Schnitzler syndrome, a very rare auto-inflammatory disease afflicting only about 300 people in the world. Kwong, exuberant, phoned Shefrin at home.

“She said, ‘I think I know what you have! And there is a treatment for it.’ I was overcome with emotion,” Shefrin recalled.

Testing the diagnosis

The syndrome was first described in 1972 by French dermatologist Liliane Schnitzler, MD. There is no known marker for the disease, which is diagnosed on the basis of a set of symptoms that include those Shefrin had. In fact, hers is a textbook case. The ultimate diagnostic test, however, is whether patients respond to treatment. Standard therapy involves using the rheumatoid arthritis medication, anakinra, which counters the effects of the inflammatory molecule, interleukin-1, thus suppressing the inflammation, which is at the core of the disease. It’s expensive, with an average wholesale price of $167 for a daily dose.

On Nov. 7, 2017, 14 long months after her symptoms first appeared, Shefrin began using the medication, injecting a single dose into the skin of her abdomen around 3:30 that afternoon.

“By 4 p.m., the rash was disappearing. The pain, which always appeared around 4 or 5 p.m., was on its way, when suddenly, it stopped,” she said. “When I woke up the next morning, the rash was completely gone. It was truly a miracle. I’ve had no pain since.” As Shefrin continued to inject herself daily with the medication, she slowly began to regain her energy, and her blood tests gradually approached normal.

“Her life is back. It’s unbelievable,” Gotlib said. “If I look over the last few years, I think this is one of the cases I’m most proud of. Right from the start, I had a degree of skepticism about what was going on. However, Bernice is the one who put it all together.”

Shefrin was Gotlib’s first Schnitzler patient but Kwong had a patient a few years ago who, in retrospect, she believes also had the disease. That woman suffered for 25 years with intense pain no rheumatologist could remedy, Kwong said. However, after starting anakinra treatment, the woman was able to return to gardening, her passion. Kwong and Gotlib both now agree that the disease is vastly under-recognized by physicians. They remain on alert for detecting other patients.

Kwong said she will never forget Shefrin and her case.

“Those moments make you step back and think, this is why I’m here — to help people in the darkest moments of their lives and to try to find some light and some answers,” Kwong said. “I’m so grateful to be in an academic center, where I have colleagues like Jason who can say, ‘Can you see this patient one more time and look at her symptoms from a different angle?’”

Shefrin has allowed Kwong to take additional skin tissue for research analysis to better understand the disease and possibly develop targeted therapies. Gotlib said he plans to sequence the roughly 23,000 genes in normal and abnormal tissues that encode for proteins, using samples from Shefrin and other patients, in a search for a mutation that might be the source of Schnitzler syndrome.

“We haven’t found the gene for this one yet. So it’s a fishing expedition,” he said.

Although Shefrin’s health will never be as good as it was before she developed Schnitzler, not a day goes by that she doesn’t think of and thank “my brilliant doctors,” Gotlib and Kwong, she said. 

She is back to sewing and knitting, playing bridge, walking her terrier, and socializing. She will need to inject anakinra every day for the rest of her life; fortunately, she has had few side effects. Without anakinra, the skin rash and severe joint pain return within hours. Because the medication suppresses her immune system, she takes precautions to protect against infection.

She said she decided to share her story in the hope of helping those who may have undiagnosed Schnitzler’s. “If just one person recognizes his or her symptoms in my illness and is able to get help, then having told my story will make it worthwhile.”