Marthe Kirkesæther Brun's doctoral thesis holds 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 appointed 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 fellow at the REMEDY research center at Diakonhjemmet Hospital. On April 25, 2024, she defended her thesis and thus 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 specialist in rheumatology, Brun became interested in patients who do not respond adequately to infliximab and other biological treatments. Two out of three patients with inflammatory joint diseases treated with these drugs achieve symptom freedom. Those who do not respond well to treatment can have significant discomfort 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 within gastroenterology and laboratory medicine at AHUS and Oslo University Hospital, respectively, were awarded support from KLINBEFORSK for the randomized controlled NOR-DRUM studies. South-Eastern Health has funded Brun's doctoral project related to these studies.
–With that, I had the opportunity to conduct research to find out what really happens when treatment with such a widely used drug as infliximab does not work, says Brun.
Antibodies prevent effect
615 patients with inflammatory bowel disease, joints or skin, treated with infliximab, from Diakonhjemmet Hospital and 20 other Norwegian hospitals, participated in the NOR-DRUM studies. The researchers found that many were treated until they were symptom-free, but that not all had a satisfactory effect. In some, the immune system formed antibodies that bound to the drug and prevented 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 examined risk factors for developing antibodies to the treatment. They found that patients with high disease activity, smokers, and patients with rheumatoid arthritis were at increased risk. They also found that the risk increased if patients did not receive additional immunosuppressive treatments or if they had breaks in their treatment with biologic 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 increased risk, she says.
Monitoring and adjustment provide better treatment
By adjusting treatment based on results from regular testing of drug levels and antibodies, more patients experienced better effects from treatment. Fewer patients experienced worsening of their disease.
“Monitoring drug levels in patients to adjust dosage may therefore be useful in patients treated with infliximab. This is especially true for 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 medications, is now routine for patients treated with infliximab. The method is also used to obtain information about the causes of poor efficacy of other biological drugs.
In other hospitals, the use of these methods is also becoming increasingly common, especially after new guidelines were published in March. These are based, among other things, on results described in articles from Brun's doctoral work.
PhD from REMEDY and Diakonhjemmet Hospital
The doctoral work is based at 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 the planning and implementation of 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 ensuring that patients have the best possible everyday life, and I enjoy clinical practice,” says Brun. Clinical research and clinical practice go hand in hand at REMEDY and Diakonhjemmet Hospital, so I envision being able to continue with research as well,” she says.
Trial lecture title
was "The overlap between axial spondyloarthritis and other inflammatory immune mediated diseases".
Supervisors, committee and dissertation director
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
Dissertation supervisor: 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/fulltext
