Scripties UMCG - Rijksuniversiteit Groningen
 
English | Nederlands

Long-term treatment of rheumatoid arthritis with rituximab and the influence on the immunoglobulin concentration

(2010) Kemperink, H.

Objective
Biologicals are drugs composed of proteins directed against specific cells or cytokines. Biologicals are making a change in the treatment of rheumatic and immunological conditions. Apart from TNF-blockers currently other targets like CD20 positive B-cells are used for the treatment of Rheumatoid Arthritis (RA). Rituximab is such a monoclonal antibody directed against B-cells. Because of the B-cell depleting properties of rituximab, the influence of this drug on B-cells and their products (immunoglobulins) is interesting. In line with the immunological mechanism, a state of hypogammaglobulinemia might occur after multiple infusions of rituximab that can cause recurrent infections. Long-term follow-up data of pivotal trial patients revealed persistence of B-cell depletion and low immunoglobulin concentration in 25% of patients. However, the accompanying rise in infection rate was not reported. That is why we investigated the influence of multiple rituximab infusions on immunoglobulin levels.

Patients and methods
Data were collected by using the DREAM (Dutch Rheumatoid Arthritis Monitoring Coalition) registry about RA patients using biologicals. Within this DREAM registry, a sufficient amount of rituximab using patients was available. We retrieved data from hospitals and we used paired univariant analysis as well as repeated measurement analysis.

Results
We collected immunoglobulin levels of 55 patients, of which 37 could be used for statistical analysis until 4 infusion courses of IgM and IgA levels and 12 for IgG levels. For IgM, a significant difference in concentration could be demonstrated for all baseline comparisons and there was also a significant decrease for course 1 compared to course 2,3 and 4. A further non-significant decrease after 4 courses was also seen. For IgA, there is a significant decrease in concentration when baseline values were compared to course 2,3 and 4. IgA levels also show a further decrease after 4 courses. IgG levels do not yet decrease significantly within 4 infusion courses of rituximab.

Conclusion
There is a significant decrease in IgM and IgA concentration when patients receive as much as 4 infusions of rituximab. In line with the immunological mechanism, IgG levels do not yet decrease after 4 courses. Our data suggest that depleting B-cells result in decreased immunological response on novel antigens (IgM and IgG). It might be hypothised if continued exposure to rituximab will result in decreased IgG levels as well affecting the immunological defense.





Gebruik a.u.b. deze link om te verwijzen naar dit document:
http://irs.ub.rug.nl/dbi/4dee3543dc87b

ID 971
Moeder ID 696
Volgorde Kemperink, H.
Naam KemperikH
Publiceren yes
OAI-naam Student_thesis
Path root/geneeskunde/2010/KemperikH/
Gemaakt op: 2011-06-07 14:28:02
Gemodificeerd op: 2011-06-07 14:28:02
Digitaal ID 4dee3543dc87b
Afstudeerrichting opleiding/afstudeerrichting 1
Studierichting Studierichting 1
Titel Long-term treatment of rheumatoid arthritis with rituximab and the influence on the immunoglobulin concentration
Ruilverkeer mogelijk no
Printen in opdracht no
Aantal pagina's 35
Publicatiejaar 2010
Taal nl
Engelse samenvatting Objective
Biologicals are drugs composed of proteins directed against specific cells or cytokines. Biologicals are making a change in the treatment of rheumatic and immunological conditions. Apart from TNF-blockers currently other targets like CD20 positive B-cells are used for the treatment of Rheumatoid Arthritis (RA). Rituximab is such a monoclonal antibody directed against B-cells. Because of the B-cell depleting properties of rituximab, the influence of this drug on B-cells and their products (immunoglobulins) is interesting. In line with the immunological mechanism, a state of hypogammaglobulinemia might occur after multiple infusions of rituximab that can cause recurrent infections. Long-term follow-up data of pivotal trial patients revealed persistence of B-cell depletion and low immunoglobulin concentration in 25% of patients. However, the accompanying rise in infection rate was not reported. That is why we investigated the influence of multiple rituximab infusions on immunoglobulin levels.

Patients and methods
Data were collected by using the DREAM (Dutch Rheumatoid Arthritis Monitoring Coalition) registry about RA patients using biologicals. Within this DREAM registry, a sufficient amount of rituximab using patients was available. We retrieved data from hospitals and we used paired univariant analysis as well as repeated measurement analysis.

Results
We collected immunoglobulin levels of 55 patients, of which 37 could be used for statistical analysis until 4 infusion courses of IgM and IgA levels and 12 for IgG levels. For IgM, a significant difference in concentration could be demonstrated for all baseline comparisons and there was also a significant decrease for course 1 compared to course 2,3 and 4. A further non-significant decrease after 4 courses was also seen. For IgA, there is a significant decrease in concentration when baseline values were compared to course 2,3 and 4. IgA levels also show a further decrease after 4 courses. IgG levels do not yet decrease significantly within 4 infusion courses of rituximab.

Conclusion
There is a significant decrease in IgM and IgA concentration when patients receive as much as 4 infusions of rituximab. In line with the immunological mechanism, IgG levels do not yet decrease after 4 courses. Our data suggest that depleting B-cells result in decreased immunological response on novel antigens (IgM and IgG). It might be hypothised if continued exposure to rituximab will result in decreased IgG levels as well affecting the immunological defense.
Nederlandse samenvatting Doel
Biologicals zijn medicijnen bestaande uit eiwitten en gericht tegen specifieke cellen of cytokinen. Biologicals hebben gezorgd voor een belangrijke verandering in de behandeling van RA en immunologische aandoeningen. Behalve Tumor Necrosis Factor (TNF) zijn er ook andere therapeutische doelen, bijvoorbeeld CD20 positieve B-cellen. Rituximab is een monoklonaal antilichaam gericht tegen B-cellen. Omdat rituximab gericht is tegen B-cellen is de invloed die rituximab heeft op het immuunsysteem interessant. Gezien het immunologisch mechanisme kan hypogammaglobulinemie ontstaan na multipele kuren rituximab. Dit kan terugkerende infecties veroorzaken. Lange termijn data vanuit de farmaceutische industrie laten persisterende B-cel depletie en lage immuunglobulinespiegels zien bij 25% van de patiënten. De daarbij verwachte stijging in infecties werd echter niet gerapporteerd. Daarom onderzoeken wij de invloed van multipele kuren rituximab op de concentratie immuunglobulinen.

Patiënten en methoden
We verzamelden data door gebruik te maken van de DREAM (Dutch Rheumatoid Arthritis Monitoring Coalition) database. Hier zijn gegevens beschikbaar van RA-patiënten die biologicals gebruiken. In deze database zitten ook voldoende rituximab-gebruikers. We vergaarden data uit ziekenhuizen en we gebruikten zowel de gepaarde analyse als de repeated measurements analyse voor de statistieken.

Resultaten
We verzamelden immuunglobulinespiegels van 55 patiënten waarvan er 37 gebruikt konden worden voor de statistische analyse t/m 4 kuren voor IgM en IgA en 12 patiënten voor IgG. Voor IgM vonden we een significant verschil in concentratie voor alle baseline vergelijkingen en er was ook een significante daling voor kuur 1 in vergelijking met kuur 2, 3 en 4. Verder werd ook een progressieve daling gezien na 4 kuren. Voor IgA vonden we een significante daling in concentratie voor de baseline waarden in vergelijking met kuur 2, 3 en 4. IgA spiegels tonen ook een progressieve daling na de 4e kuur. IgG spiegels laten geen significante daling zien na 4 kuren rituximab.

Conclusie
Er is een significante daling in IgM en IgA concentraties wanneer patiënten 4 kuren rituximab toegediend krijgen. Zoals verwacht, gezien het immunologische mechanisme, dalen IgG spiegels nog niet binnen 4 kuren. Onze data suggereren dat B-cel depletie resulteert in een verminderde immunologische respons. Mogelijk zal langer durende blootstelling aan rituximab leiden tot verlaagde IgG spiegels en zal hierdoor de immunologische verdediging tekort schieten.
Onderwijsinstelling Medical Sciences
Type embargo abstract openbaar, scriptie op aanvraag
Auteur(s) Kemperink, H.
UMCG begeleider(s) Laar Prof. Dr. M.A.F.J. van de
Begeleider(s) opleidingsinstelling Laar Prof. Dr. M.A.F.J. van de
Auteur(s) Kemperink, H.
UMCG begeleider(s) Laar Prof. Dr. M.A.F.J. van de


 
To top