Therapy

Infliximab towards optimizing infliximab therapy in sarcoidosis 

This study investigates the correlation between biomarkers, infliximab-levels, formation of anti-infliximab antibodies and responsiveness to infliximab treatment.

Sarcoidosis is a systemic granulomatous disease that predominantly affects the lungs and the lymphatic system. Corticosteroids and methotrexate present the mainstay of treatment for sarcoidosis. Due to the non-specificity, long-term toxicity and limited efficacy of these therapies, more effective and safer therapies are needed. As the cytokine tumor necrosis factor (TNF)-α is critical to the development of the granulomatous inflammation in sarcoidosis, the TNF-α inhibitor may well serve as an alternative treatment. The chimeric anti-TNF-α monoclonal IgG1 antibody 'Infliximab' neutralizes the biological activity of soluble and membrane-bound TNF-α.

Previous studies with infliximab in severe and refractory sarcoidosis show that most sarcoidosis patients achieve at least a partial clinical response to infliximab. However, around 30% of the treated patients are not responding at all. Currently, no clear predictors of responsiveness are available. The hypothesis to be tested in this study is that serum infliximab concentrations and anti-infliximab antibodies are responsible for the inter individual variation in response to infliximab therapy.

Project group: A. Vorselaars, C.H.M. van Moorsel, V. Deneer, A. Claessen, G. Rijkers, J.C. Grutters

More information to be obtained from primary investigator:
Renske Vorselaars, MD
a.vorselaars@antoniusziekenhuis.nl  

Infliximab tailor-made medicine in interstitial lung  diseases: pharmacogenetics and pharmacokinetics 

The main goal of this project is to personalize treatment in interstitial lung disease, especially in sarcoidosis. For instance, if sarcoidosis patients do not respond to corticosteroids or if they experience severe side effects, medication is often switched to methotrexate. Next, if response is still insufficient, infliximab is added. This project uses pharmacogenetics to predict the response to these second and third line treatments in sarcoidosis. Furthermore, pharmacokinetics of and immunologic response to infliximab in sarcoidosis are part of this study. In this light a randomized, double blind, study will be performed which hypothesizes that a serum concentration guided dosing of infliximab is not inferior to standard dosing based on body weight in patients with severe sarcoidosis. Results of this study will ultimately lead to optimizing personalized treatment.

Project group: H. Crommelin, V. Deneer, C.H.M. van Moorsel, A. Claessen, J.C. Grutters

More information to be obtained from primary investigator:
Heleen Crommelin, MSc
h.crommelin@antoniusziekenhuis.nl

Sarcoidosis and quality of life 

The orphan disease sarcoidosis induces a major reduction in quality of life (QOL) and loss of productivity in predominantly young adults. This project examines whether subtle suppression of the initial inflammatory process of sarcoidosis by dexamethasone therapy achieves significant alleviation of acute symptoms, improvement of QOL and decline in sick leave. Moreover, the study determines whether this early intervention prevents disease progression eventually reducing total health care costs.

In sarcoidosis multiple organs are affected by inflammation. The cause of the disease is unknown and no curative medication exists. Most patients are diagnosed between the age of 20-40 years and sarcoidosis invalidates their lives from that time on. Although curative therapy is not on hand, immunosuppressive drugs may control the symptoms of the disease. These symptoms are caused by the inflammation in multiple organs, foremost lungs and lymphoid system. However, 90% of the sarcoidosis patients receives no immunosuppressive medication during the first months after diagnosis, even though the immune system is then highly activated and patients suffer from severe malaise and pain. This wait-and-see policy is common international practice, but scientific grounds and official guidelines are lacking.
Our project entails a randomized, double-blind and placebo-controlled trial that tests the effectiveness of a low-dose dexamethasone therapy during the first 6 months after diagnosis. This low-cost intervention is available for every patient and easy to implement in medical practice. Moreover, study outcomes will contribute to establish grade A therapy guidelines that are lacking at the moment.

Project group: R. Vis, E. van de Garde, A. Hövels (UU), I.H.E. Korenromp, J.C. Grutters

More information to be obtained from investigators:
Roeland Vis, MSc
r.vis@antoniusziekenhuis.nl
Ingrid Korenromp, PhD
i.korenromp@antoniusziekenhuis.nl  

Rituximab in life threatening therapy resistant progressive interstitial pneumonitis  

This study comprises a trial with rituximab in interstitial pneumonitis (IP) in immune mediated inflammatory diseases (IMID's). IMID's include a broad spectrum of inflammatory disorders, which are one of the world's leading causes for physical and social disabilities accompanied with high medical costs. This project will address rare IMID's involving the lungs. When left untreated, interstitial pneumonitis (IP) can lead to poor quality of life and increased mortality. Current treatments with various immunosuppressive drugs are unable to cure the disease but may be able to slow it down. However, a small group of patients does not respond sufficiently. Those with advancing IP will ultimately risk respiratory failure and death. Even though lung transplantation could be a final option, the latter is an extremely expensive procedure with limited survival benefits. Thus, new therapeutic options are needed.

Recent studies focusing on immune mediated diseases show encouraging results in suppressing the dysfunctional B lymphocytes. This can be achieved with the administration of rituximab, a widely used monoclonal antibody. Although preliminary results are promising, not all patients benefit from rituximab treatment. In this trial we will use an elaborate imaging technique to follow the distribution of rituximab in the patient. We aim to show in which patients rituximab stabilizes disease activity and improves lung function. If so, this could provide the patient with a new life saving treatment option.

Project group: H. Adams, R. Keijsers, E. van der Garde, Y.A. de Man, C.H.M. van Moorsel, A. Claessen, J.C. Grutters

More information to be obtained from primary investigator:
Human Adams, MD
h.adams@antoniusziekenhuis.nl