In Marthe Kirkesæther Brun's doctoral work lies the key to preventing disease flare-ups in individuals with chronic inflammatory disease: The dosage of the biological drug infliximab should be adjusted over time, based on measurements of the drug's concentration in the blood.
From left, co-supervisors Johanna E. Gehin, Kristin K. Jørgensen, Guro L. Goll, newly minted doctor, Marthe Kirkesæther Brun, main supervisor Silje W. Syversen and co-supervisor Espen A. Haavardsholm. Photo Diakonhjemmet hospital/Kathrine Daniloff
She has called the thesis Infliximab therapy in immune-mediated inflammatory diseases: Immunogenicity and proactive therapeutic drug monitoring
The research led to new guidelines
In 2019, Marthe Kirkesæther Brun started as a full-time PhD scholar at the research center REMEDY at Diakonhjemmet hospital. On 25 April 2024, she defended her dissertation and thereby completed her doctorate. The research has resulted in new treatment guidelines for patients with inflammatory joint disease. The guidelines involve monitoring and adjusting medication, known as therapeutic drug monitoring.
Medical revolution for inflammatory diseases
As a doctor specializing in rheumatology (LIS), Brun took an interest in patients who do not get the full effect of infliximab and other biological treatment. Two out of three people with inflammatory joint diseases who are treated with these medicines achieve freedom from symptoms. Those who do not respond well to the treatment can have major problems and risk developing joint damage.
Same treatment - different effect
In 2016, researchers from Diakonhjemmet Hospital, Silje Watterdal Syversen, Guro Løvik Goll and Espen A. Haavardsholm, together with researchers in gastromedicine and laboratory medicine at AHUS and Oslo University Hospital respectively, were awarded support from KLINBEFORSK for the randomized controlled NOR-DRUM studies. Helse Sør-East has funded Brun's doctoral project which is linked to these studies.
- This gave me the opportunity to do research to find out what actually happens when the treatment with such a widely used drug as infliximab does not work, says Brun.
Antibodies prevent action
615 patients with inflammatory bowel, joint or skin disease, treated with infliximab, from Diakonhjemmet hospital and 20 other Norwegian hospitals, participated in the NOR-DRUM studies. The researchers learned that many people are treated until they become symptom-free, but that not everyone gets a full effect. In some, the immune system formed antibodies that bind to the drug and prevent it from working.
- These antibodies are an important reason why patients do not get a good enough effect from the treatment, says Brun.
Causes of antibodies
The researchers also investigated risk factors for developing antibodies against the treatment. They found that patients with high disease activity, smokers and patients with rheumatoid arthritis had an increased risk. Furthermore, they found that the risk increased if patients did not receive additional immunosuppressive treatments or if they had breaks in treatment with biological medicine. The risk of antibodies was also higher if they were treated with low doses of infliximab or had low levels of infliximab in their blood.
- In addition, we found that a genetic variant, the tissue type antigen HLA-DQ2, was associated with an increased risk, she says.
Monitoring and adjustment provide better treatment
By adjusting the treatment, based on results from regular testing of drug levels and antibodies, more patients got a better effect from the treatment. Fewer became worse from the disease.
- Monitoring the drug level in patients to adjust dosage can therefore be useful in patients treated with infliximab. This particularly applies to those who have risk factors for developing antibodies, explains Brun.
From research to clinical practice
At Diakonhjemmet hospital, therapeutic drug monitoring, with regular measurements to adjust the drugs, is now routine for patients treated with infliximab. The method is also used to obtain information about the causes of poor effects of other biological medicines.
In other hospitals, it is also increasingly common to use these methods, especially after new guidelines were published in March. This is based, among other things, on results described in the articles from Brun's doctoral work.
PhD from REMEDY and Diakonhjemmet hospital
The doctoral work originates from the Diakonhjemmet hospital and the Center for treatment of Rheumatic and Musculoskeletal Diseases (REMEDY). There has been close collaboration with the department of gastroenterology at Ahus and the department of medical biochemistry at Oslo University Hospital. In addition, departments from all over the country have been involved in planning and carrying out the NOR-DRUM studies.
The way forward
Brun is now resuming his specialization in rheumatology at Diakonhjemmet hospital after the interruption in connection with his doctoral work.
- I want to contribute to patients having the best possible everyday life, and I enjoy clinical practice, says Brun. Clinical research and clinical practice go hand in hand in REMEDY and Diakonhjemmet hospital, so I envision myself also being able to continue with research, she says.
The title of the trial lecture
was "The overlap between axial spondyloarthritis and other inflammatory immune mediated diseases".
Supervisors, committee and dissertation supervisor
Supervisors: Silje Watterdal Syversen, Guro Løvik Goll, Espen A. Haavardsholm, Kristin Kaasen Jørgensen and Johanna E. Gehin
Judging committee: Carl Turesson, Diane van der Woude and Berit Flatø
Disputation leader: Marte Lie Høivik
The articles from the doctoral project:
- Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients with Immune-Mediated Inflammatory Diseases, A Randomized Clinical Trial: https://jamanetwork.com/journals/jama/fullarticle/2787318
- Risk factors for anti-drug antibody formation to infliximab: Secondary analyzes of a randomized controlled trial: https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13495
- HLA-DQ2 is associated with anti-drug antibody formation to infliximab in patients with immune-mediated inflammatory diseases: https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13616
- Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyzes of the randomised, controlled NOR-DRUM trials: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913 (23)00341- 7/full text
