Photo by Donn Jones

Growing Pains

Published on August 30th, 2021 by Christina Echegaray.

Nyla Wright wants to live the carefree life of a 16-year-old. Her family and close-knit group of friends want that for her too. But Nyla, who has suffered from the chronic autoimmune disease lupus since she was 9, has days where she hurts so badly, she can’t get out of bed, wash or dress herself.

On those days “my pain is a 10,” she says. “It’s terrible. I’ll be having a normal day, and the next day my friends are like, ‘where’s Nyla?’ And I’ll be gone for two weeks, three weeks,” she said.

When she has a flare (an unpredictable eruption of the disease), “she hurts all over,” says her mom, Sarha. “Her body hurts. Her throat hurts. She can’t swallow. It’s like her body goes into attack. That’s the way she explains it to us.”

And that’s exactly what’s happening.

Systemic lupus erythematosus (commonly known as lupus) is a disease that causes the body’s immune system to attack its own cells and tissues. It results in episodes of inflammation to various parts of the body and can affect the joints, tendons and skin. It can cause rashes, fatigue, pain and fever, and also affect blood vessels and organs such as the kidneys, heart, lungs and brain.

Nyla, who lives in Meridianville, Alabama, a suburb of Huntsville, is one of hundreds of children and teens treated by the Division of Pediatric Rheumatology at Monroe Carell Jr. Children’s Hospital at Vanderbilt for autoimmune diseases that affect multiple organs, including lupus, juvenile idiopathic arthritis, dermatomyositis and vasculitis.

“The diagnosis of many of these conditions can be difficult because symptoms can be similar to other disorders,” said Brent Graham, MD, associate professor of Pediatrics, director of the Division of Pediatric Rheumatology and Nyla’s physician. There’s a good bit of medical detective work involved in a diagnosis, as physicians take a thorough medical history of the patients, then do a head-to-toe exam to collect clues.

“Basic science advances have improved our ability to diagnose and treat our patients in a more precise way,” Graham said. “The most important thing is to get accurate and early diagnosis and treatment and have the ability for good follow-up.”

 

‘Lupus looks very different in different people’

Nyla was 9 when she complained that her chest was hurting. Sarha took her to her pediatrician who thought she might have reflux and prescribed a reflux medication. That night, she felt worse and began to run a fever. The fever climbed to almost 104 degrees as her mom alternated ibuprofen and acetaminophen to try to bring it down. Nyla fell asleep, then got up and had a seizure. Her mom called 911, and she remained in the hospital in Huntsville for three days where she was diagnosed with lupus.

She was sent to a pediatric rheumatologist at another center, but the family wanted a second opinion, and she was able to see Graham at Children’s Hospital the next day.

“We heard what they both had to say, then we asked Nyla who she was most comfortable with, and she said Dr. Graham,” said Sarha. Graham has been Nyla’s physician for the past seven years.

“Lupus looks very different in different people. It’s a very heterogenous disease,” said Alaina Davis, MD, a pediatric rheumatologist and assistant professor of Pediatrics at Children’s Hospital. “A lot of the symptoms are very non-specific, which makes it challenging to recognize and diagnose. Kids present with persistent fevers, rashes triggered by the sun and true arthritis. They can get muscle inflammation that results in achiness and weakness and get sores on the roof of their mouth. Oftentimes, liver and kidney effects are not something the patient can feel, so you need bloodwork to look for that,” she said.

Davis said there’s not a single blood test or X-ray that can provide a diagnosis.

“You might see ulcers in the mouth, and you can get blood tests and X-rays to help support the diagnosis of lupus, but it’s a combination of things that results in a diagnosis,” Davis said.

Children with lupus have more aggressive disease than their adult counterparts, and often present with organ damage, she said. It requires timely and aggressive immune suppression medication to get the inflammation under control and protect organs. Sarha said that Nyla had heart and lung involvement early in her disease, and it’s a constant readjustment of therapies to make sure that her organs are not impacted during a flare.

Lupus occurs most often in young women in their late teens (usually older than 15) and adult women younger than 45. It also affects more African Americans, Asian Americans, Hispanics and American Indians than whites.

The cause of lupus isn’t known, but experts think it may be a mix of genes and other factors, including being exposed to the Epstein-Barr virus (which causes mononucleosis) and other environmental factors that aren’t yet known.

It’s treated with steroids during the acute phases. “They work really quickly, and they’re very strong, but they have a lot of side effects, especially in the long term, in terms of metabolism and bone health. So, we try to use the lowest dose possible for the shortest period possible,” Davis said, adding that in the early phases of treatment, higher doses, both oral and intravenous, may be necessary.

“We can control inflammation to prevent complications from the disease, but that requires the patient being adherent with a complex medical regimen and frequent doctors’ appointments. The disruption of having to come to recurring appointments and the responsibility of taking a medication two, and up to three, times a day can be really challenging,” Davis said. “Some of the complications of lupus are things you can’t see or feel (silent organ involvement). By the time a patient realizes it’s there, it’s too late. The damage is done. We can control inflammation, but we can’t reverse damage. Having lupus requires taking a medication every day, even if you feel OK, and that can be hard for a teenager to do when they want to fit in with their peers.”

Most patients with lupus take hydroxychloroquine, a drug commonly used to treat malaria. It has been shown to reduce flares in people who have lupus. “It’s really important they stay on hydroxychloroquine for life. If they stop it, they’re at an increased risk for their disease activity increasing again,” Davis said.

Nyla, one of about 100 young patients with lupus treated at Children’s Hospital, has been treated with steroids, both oral and intravenous, as well as hydroxychloroquine and other steroid medications that change based on whether her disease is stable or flaring.

Patients may also need to see other specialists when organs like the heart and kidneys become affected.

“Even though we don’t have a true multidisciplinary clinic, we work really hard to make sure the patient can see everyone they need to see in one day,” Davis said. The rheumatology team works closely with nephrology and other teams due to the multisystem nature of lupus.

And the team helps when it’s time for teens to transition from pediatric to adult care.

There are about 1.5 million cases of lupus reported in the United States. Childhood cases (those diagnosed before age 18) represent about 15-20% of patients. Davis said the disease may be present in childhood but not diagnosed until adulthood, so it’s hard to be certain how many cases are actually diagnosed during childhood and adolescence.

 

Juvenile Idiopathic Arthritis

Most of the patients seen in the Pediatric Rheumatology clinic (about 500) have juvenile idiopathic arthritis (JIA), the most common type of arthritis in children and teens. There are about 200,000 cases reported each year in the United States. JIA, formerly called juvenile rheumatoid arthritis, typically causes joint pain and inflammation in the hands, knees, ankles, elbows and/or wrists. But it may affect other body parts too.

JIA occurs when the immune system, which is supposed to fight invaders like germs and viruses, gets confused and attacks the body’s cells and tissues, causing the body to release inflammatory chemicals that attack the synovium (tissue lining around a joint).

The word “idiopathic” means unknown, and researchers aren’t sure why children develop JIA. It’s believed they have certain genes that are activated by a virus, bacteria or other external factors. But there is no evidence that foods, toxins, allergies or lack of vitamins cause the disease, according to the Arthritis Foundation.

Research is also an important component of the Division of Pediatric Rheumatology, which actively collaborates with the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the Pediatric Rheumatology Collaborative Study Group (PRCSG) to study multiple rheumatic diseases. There are active clinical research programs in systemic lupus and medication adherence and musculoskeletal pain as well as active quality improvement initiatives in juvenile idiopathic arthritis, lupus, mental health and transition care.

Basic research is also important. Anna Patrick, MD, PhD, assistant professor of Pediatrics, is establishing a program to improve the understanding of lymphocytes in JIA, a type of immune cell that is made in the bone marrow and found in the blood and lymph tissue.

Like lupus, there’s no single test that can confirm a diagnosis of JIA, because symptoms may be similar to other conditions. It’s confirmed by taking a thorough history and examination.

But a quick and early diagnosis and the ability to get good follow-up care can make a difference in the trajectory of the disease, Graham said.

“At this point, debilitating juvenile arthritis is extremely rare, but access to care is critical,” Graham said. “There are numerous treatments, and not all patients respond to first-line or second-line treatments, but there are options.”

Brent Graham, MD. Photo by Susan Urmy.

Most patients with JIA will have to stay on medicine for many years, sometimes for life, Graham said. Medications range from nonsteroidal anti-inflammatory medications to powerful disease-modifying antirheumatic drugs (DMARDs) and other immunosuppressive medications.

“Medicines have really advanced, so we have multiple biologic medicines that are effective and have low side effects, prevent damage and help patients have a really good quality of life. Many of our patients play sports, dance, are active and do whatever they want to do.”

Siblings Chase and Allie Borregard of Owensboro, Kentucky, are great examples of that, Graham said.

In 2017, Allie was 10 when she was diagnosed with oligoarticular arthritis, the most common and mildest form of JIA. Chase, now 12, was diagnosed later that year with polyarticular arthritis, affecting multiple joints. He was 8.

Both play youth hockey. Allie, now 14, attends

Selects Academy, a residential hockey program located at Bishop Kearney High School in Rochester, New York. Her 16U division team won the New York state championship in April and went on to compete in the USA Hockey Nationals. Chase, a sixth grader, plays for the Tri-State Spartans AAA hockey team.

Allie’s arthritis, which began with a swollen knee, has been managed well with medication; Chase’s has been a little more of a struggle to manage, says their mom, Andrea Borregard. It’s also likely that Chase had JIA for a couple of years before he was diagnosed. He had been seeing a specialist for about two years, who had not been able to pinpoint what was wrong.

Allie was already a patient of Graham’s when Chase was diagnosed. Chase became his patient as well.

She takes two medications to keep her arthritis under control — methotrexate, a DMARD, and an oral anti-inflammatory drug.  “Everything that’s worked for Allie has not worked for Chase. Allie’s was so easy to treat. Chase’s was not. We’re dealing with a different beast here,” Andrea said.

Allie, 14, and Chase Borregard, 12. Photo by Erin O. Smith.

After trying several medication combinations that didn’t work, or caused too many side effects, Chase’s arthritis is currently being managed with an injection of tocilizumab and an oral medication, leflunomide, both DMARDs.

“Chase has gone from hurting when he walks to playing the highest level of youth hockey. Both of my kids are very active and get to go and do. They’re not pain free all the time, but they know how to manage it and live with it. They know when to push and when to rest. They wouldn’t be doing any of that if it weren’t for the care they’ve gotten from Dr. Graham and Children’s Hospital,” Andrea said.

“For me, as a mom trying to manage two very different cases of arthritis, having complete confidence in the wonderful physician caring for my kids has made a huge difference. I trust him, and he’s been great.”

 

Helping fill the need

The Borregards travel about two hours to Nashville to see Graham. Patients in other parts of the country may have to travel longer distances to see a pediatric rheumatologist.

Finding one close by isn’t always easy, said Alisa Gotte, MD, a pediatric rheumatologist at Children’s Hospital, associate professor of Clinical Pediatrics and director of the Pediatric Rheumatology fellowship program. Most pediatric rheumatologists are located at larger academic medical centers, she said.

In the most recent analysis available, a 2015 American College of Rheumatology study, there were only 287 pediatric rheumatologists offering clinical care in the United States. The projected need was 382. “So, we were already working at deficit,” Gotte said, adding that the gap is estimated to keep widening. In 2025, the projected workforce is 243 (down from 287 due to the fact that pediatric rheumatologists tend to be older and many may be retiring), and the projected need is 434. In 2030, the workforce is expected to be down to 231, with 461 needed.

To help fill the need, Vanderbilt began a three-year accredited fellowship program in 2014. Alaina Davis, MD, now on the faculty, was the first graduate of the program.

“Our training program emphasizes the importance of training new people so maybe our workforce numbers will improve instead of going down,” Gotte said. The Children’s Hospital program has four fellows during the current academic year. Recent fellowship graduates from Vanderbilt have opened practices in Kingsport, Tennessee, and in Columbia, South Carolina.

The first year of the program is a clinical year where the physician takes care of patients. During the second and third years, they continue their clinical education but add a scholarly activity. “Pediatric rheumatology is a field where we need lots of research to explore diagnosis and find better treatments,” Gotte said. Recent research by fellows at Vanderbilt includes a project with medical students to expose them to pediatric rheumatology early in their medical education; basic research in a lab; and a clinical research project looking at depression and mental health disorders in patients with lupus.

Nine states, mostly in the West, have no pediatric rheumatologists. If you don’t live near one, it raises the chance that a child goes undiagnosed, Gotte said. The average number of miles a patient must travel to see a pediatric rheumatologist is 57, about twice the distance to see other specialists.

 

‘You have to keep pushing’

Nyla, who travels about an hour and 45 minutes for her appointments at Children’s Hospital, says having lupus, frequent medical appointments, and a complicated regimen of medication is hard on her academically and socially.

“I’ll be gone for two weeks, three weeks (when her disease flares) and there’s a boatload of schoolwork to do. Everything is piling up, and all I can do is blink. It sucks to be 16, and I can’t drive anywhere and go and have fun. Sometimes it’s hard to explain to my friends what happens to me, but they understand, and they still love me.”

The COVID-19 pandemic has added an extra layer of complexity to her life. She has had to wear a mask at school and in public for years during flu season, but last year had to switch to remote learning and to always wearing a mask when outside her home.

Her mom gives her this advice: “It’s been a rollercoaster for us, but I always say, you can deal with a lot of things given to you, and you have to keep pushing.”

And Nyla does.

She tries to accomplish a lot on the days she is feeling well. Prior to the pandemic she joined a group of teens with lupus to visit members of U.S. Congress in Washington, D.C., to lobby for more money for lupus research. She hopes to do it again. “It was awesome,” she says.

And over the last year of quarantine, she taught herself to crochet. “I got bored and needed something to keep my mind off my schoolwork and having lupus,” she said. She’s accomplished in amigurumi (the Japanese art of crocheting tiny dolls and animals), has an Instagram account devoted to her art, and plans to open an Etsy shop.

“I really love it,” she says of her new hobby.