A Rare Disease, a Global Search and a Happy Outcome

Posted on Jan 09, 2018

Jennifer Leiding, M.D., with Nicholas

Jennifer Leiding, M.D., from John Hopkins All Children's Hospital, met 8-year-old Nicholas during a typical new patient meeting. Nicholas had visited doctors around the country. No one had been able to diagnose him, so he was referred to Leiding as an expert in immune deficiencies.

After reviewing his complex clinical history—which included a hematopoietic stem cell transplant, chronic colitis, early onset type 1 diabetes and hypothyroidism—Leiding determined Nicholas had a GOF-STAT1 (gain-of-function signal transducer and activator of transcription-1) gene mutation that caused his immune system to attack healthy cells as well as harmful ones.

Leiding, a pediatric immunologist and allergy specialist in the Johns Hopkins All Children’s Cancer & Blood Disorders Institute and the University of South Florida (USF) Morsani College of Medicine, was familiar with various clinical manifestations of the disease as well as ongoing investigations of treatments. The St. Petersburg, Florida, native immediately recognized Nicholas' case as remarkable. He had received a stem cell transplant at 3 years old, and contrary to all published case studies at the time, he lived.

Patients such as Nicholas had few treatment options to work with. While some physicians had tried stem cell transplant as a last-hope option, there was significant reluctance to use this therapy because nearly all the patients died shortly after transplant. But standing before her was living proof that it could work.

Leiding knew Nicholas' story needed to be shared.

Global Hunt for Data

At first, the goal was to get the word out that a GOF-STAT1 patient who was transplanted had lived. After compiling a thorough case study, Leiding and Troy Torgerson, an immunologist at Seattle Children's Research Institute, sought additional patients to include in a research article. Months of soliciting data from around the globe resulted in the clinical histories of 15 patients, all with confirmed GOF-STAT1 mutations like Nicholas, all who received stem cell transplants.

The new dataset changed the goal of the research.

"Once you start analyzing the data," Leiding says, "you see the answer before you even ask the question. The data tells you what you need to be asking."

Patterns emerged from the results, which led to a set of recommendations on which patients should be considered for transplant, when and how. What started as a singular case study grew into groundbreaking research that will aid physicians in better treating this rare disease.

Research Results

Leiding's research, which was published in the Journal of Allergy and Clinical Immunology, suggests that stem cell transplant is a viable and curative option for some patients with GOF-STAT1 mutations. The transplant was not an elective procedure for any of these patients. It was attempted as a life-saving effort in the direst of cases, and 40 percent of the patients lived.

Perhaps more important, the data reveal insights into which variables matter most. The genotype and phenotype of the disease and the conditioning regimen did not have much impact on survival, but age at the time of transplant was important. Younger patients fared significantly better. Patients with active hemophagocytic lymphohistiocytosis (HLH), a life-threatening blood disorder, fared worse. But some patients with IPEX-like syndrome—combined immunodeficiency, life-threatening infections and severe autoimmunity—could be cured, quickly and permanently.

Investigating Rare Diseases

Leiding spends her days trying to understand the mechanisms that cause immune disruptions and the pathophysiology behind them. Advances in genetic testing and diagnostics are helping to identify where the problems stem from, but more information is needed to better treat the patients.

To become a leader in this field, Leiding trained in a three-year fellowship with the National Institute of Allergy and Infectious Diseases. There she split her time between clinical training and research investigation in the Laboratory of Clinical Infectious Diseases (LCID).

"In the LCID, we saw patients from all over the world with all sorts of different immune deficiencies and I really learned how to diagnose well, treat well, and how to learn from the patient to better treat other patients," Leiding says.

When working with rare diseases—including those called “orphan diseases” because they affect fewer than 200,000 people nationwide— simply compiling enough information to develop recommendations is an enormous undertaking. But this time, it had an equally enormous payoff. This research brought a viable treatment option back to the table. Physicians developing treatment plans now have data and recommendations to refer to. And researchers interested in conducting prospective studies have a starting point.

As an advocate for patients with rare disorders, Leiding relies on her training and the unique skill set required to develop novel treatment plans.

As Leiding says, "they teach us how to treat them, and then others like them."

This story first appeared in Leading Care magazine.

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