3 New treatment approches –biologics
6.6 Adverse events
6.6.4 Prolonged B cell depletion
Reports from the lymphoma literature have also described prolonged B cell depletion but in most cases after repeated courses of RTX where RTX have rather been used as maintenance therapy during the follow-up period [146]. Reduced levels of IgM have been reported with repeated courses of RTX but no increase in the levels of infections has been observed. With discontinuation of RTX a return of B cells and recovering of IgM levels are seen. Apart from our own study (paper IV) no reports on prolonged B cell depletion after a single course of RTX in autoimmune disease have been published.
In these two cases normal Ig levels were found despite several years of B cell depletion.
BAFF levels were measured serially up to 6 months in one of the patients and found to be raised after therapy. Several years before RTX treatment that same patients underwent splenectomy due to resistant thrombocytopenia. Splenic marginal zone B cells appear to be related to peripheral blood IgM+, CD27+ B cells (non-switched memory B cells) which represent approximately one third of circulating B cells in normal adults and are known to be absent in patients who have undergone splenectomy [152]. Treatment with RTX is associated with depletion of both switched and non-switched memory B cells and depletion of IgM+, CD27+ B cells appear to be especially prolonged [121]. Thus the splenectomy in combination with RTX treatment might to some extent explain the prolonged B cell depletion in this patient.
7 CONCLUDING REMARKS AND FUTURE PERSPECTIVES
The disappointing results from the two industrial sponsored RCT on RTX as add on treatment to standard of care in;
1) mild to moderate SLE without nephritis or neurological manifestations (EXPLORER) and
2) the study on proliferative LN (LUNAR)
brings many questions about RTX treatment and study design into consideration.
• Is it really not working?
• Is something wrong with the study design o Wrong patient population
Disease manifestations
Severity of disease
Treatment protocol
• Concomitant immunosuppressive treatment
• GC dosages
In our clinic we now have eight years of experience of using RTX in combination with low dose IV CYC in patients with severe and resistant SLE. We have currently treated over 40 patients and the majority has achieved an acceptable clinical response with disease control over longer or shorter periods of time. However, non-responders, mainly patients with extremely complicated and non-typical disease with various immunological changes have been seen.
Nine patients are successfully retreated following a flare and most of them have had a more rapid and pronounced response after the second course of RTX.
We have most faith in the treatment of the patients with LN were we have with rigorous follow up selected data on clinical as well as histological response. In this group of resistant patients we have demonstrated very good clinical results. It is important to notice that at the Karolinska University Hospital we have good experience in managing patients with SLE and LN. The patients are closely followed and we aim at a minimal time lag for performance of renal biopsy and initiation of treatment. This and a close monitoring during follow-up may in some setting explain the good results.
We have experienced the treatment to be relatively safe and adverse events reported at the same incidences as by others. However, the number of patients treated today is far too small to draw any definitive conclusions on adverse events. Of course there must be vigilance for drop in total Ig and infections as well as the total immunocompetency of the patients during long term follow up.
Little is still known about repeated courses of RTX treatment in SLE although re-treatment is commonly practiced among hematological patients. The effect of the treatment in these two different disease populations is difficult. Hematologic patients
have totally different prerequisite for the immunological response though often heavily immunocompromized due to malignant disease and aggressive chemotherapy.
In RA re-treatment RTX appears to be relatively safe although a drop in both IgM and IgG are seen after repeated courses. A trend toward increased frequency of serious adverse events with low IgG values have been noted (van Vollenhoven et al, in press).
Despite the disappointing results from RCT I believe with the support of our experience and data that RTX+CYC can be a treatment alternative for patients with severe and resistant SLE. I have especially hope for the treatment in LN where our short and long term data have supported good clinical and histological outcome in these previously therapy resistant patients. However in light of the lacking support of RCT and the small and heterogeneous nature of the available open labeled trials I would presently not recommend this treatment to therapy naïve patients nor patients with milder disease forms.
Vigilance for long term effects on the immune system and immunocompetency of patients is mandatory. All patients should prior to RTX treatment achieve vaccination with pneumococcal vaccine and in exceptional cases even against H. influenza as well as influenza vaccine if in season [152, 188]. It is recommended that patients at high risk for hepatitis B infection should be screened before treatment [152]. In the future more studies are needed on the immunological effects of RTX especially regarding the changes in different cell types and cytokines. Weight should be put on functional test to better understand the possible mechanisms underlying effect and risk of adverse events.
In the future we might see studies on combination treatment with RTX. A combination with treatments that would block survival niches for B cells such as anti-BLyS could be feasible. The aim would be to get more profound and long lasting B cell depletion and thus a better prerequisite for resetting the immunological balance.
Rituximab can be effective in a subgroup of patients with severe resistant SLE. The concomitant medication with cyclophosphamide and glucocorticoids is thought to play an important role with possible synergistic effects.
8 ACKNOWLEDGEMENTS
Ronald van Vollenhoven my main supervisor for introducing me to science and during my years at the clinic guiding my clinical and scientific steps along the road. For excellent knowledge and skills and for encouragement, showing enormous patience and for being positive in every situation. For all the times I have discussed practical clinical or scientific issues and you always had the time to listen and give constructive feedback. All the things that were complex and difficult always seemed clear and simple after discussing them with you. Thank you for your warm and caring personality.
Iva Gunnarsson my co-supervisor and mentor in many ways. For your clear visions, practical thinking and planning skills. For being a good supervisor, gentle and firm at the same time – newer loosing sight of the goal. Tracking me back on the road whenever I got lost in the woods. For being a good friend, a god listener and not the least for giving me advice on how to act on scientific meetings – I have really learned a lot – I now know what it is really all about!!
Lars Klareskog my co supervisor for creating a good scientific atmosphere at the clinic and making it possible for so many of us to be introduced to the world of science.
For working hard on creating a communicative environment between the lab and the clinic, making an extraordinary interactive scientific environment.
Birgitta Sundelin my co-author for your excellent skills in nephropathology, for guiding me in the histological world and for the interesting and guiding discussions.
Eleanor Gullström for taking care of all the logistics around the patients, planning and organizing. Keeping track of everything when I lost it. I’m not sure there had been any thesis without you. Many Thanks!
My co-authors: Agneta Zickert, Elisabet Welin-Henriksson and Anke Risselada for helping with collecting data and contributing to the scientific discussion.
Eva Jemseby for always being ready to take care of the samples.
Elisabet Svenungsson for educating clinical discussion and your excellent clinical skills when it comes to patients with SLE and systemic autoimmune diseases. For pleasant company on congress trips. Brigitte Dupré for nice talks and good friendship.
Vivianne Malmström, Christina Trollmo and Therese Wallerskog for sharing interest in the immunological changes in patients with SLE. For good discussions and important input.
Johan Bratt present head of the Rheumatology Unit for assuring positive working atmosphere.
Colleagues and friends at the clinic for creating a very good working atmosphere and making the Unit of Rheumatology at the Karolinska an exciting and enjoyable place to work: Lena Björnådal, Birgitta Nordmark, Ingrid Lundberg, Anders Harju, Per Larsson Maryam Dastmalchi, Marika Kvarnström, Tomas Zweig, Jon Lampa, Erik af Klint, Bo Ringertz, Ralph Nisell, Staffan Lindblad, Esbjörn Larsson, Ulf Nyman, Anca Catrina, Lara Dani, Cecilia Carlens, Johanna Gustafsson, Ola Börjesson, Christina Stranger, Johan Askling, Hamed Rezaei, Guo-Zhong Fei, Jenny Augustsson, Vilija Oke, Louise Ekholm.
Especially Christina Dorph, Annica Nordin, Petra Neregård for support and nice talks and my Icelandic colleagues Sædís Sævarsdóttir and Guðrún Reynisdóttir for encouragement, kindness and good times.
Eva Daleskog for taking care of the logistics around my patients in the open ward and for trying hard to make my days easier and better in every way.
Gunnel Bermerfeldt and Susanne Karlfeldt for always giving excellent support.
Sigrid Lundberg for being a good friend and for guiding me in the nephrological matters.
My dear friends Gerdur and Inga for guiding examples that career and family can both fit in a woman world. Inga for all our talks and your always good and clear advises. No issues have been too simple to discuss with you. Gerdur for helping me and
encouraging in many different situations.
Friends and colleagues, Sigurður – for encouraging talks these last weeks and the supportive Icelandic attitude “þetta reddast”, Sunna, Jói, Guðrún, Sigíður, Jóhanna and Siggi and all other colleagues and friends from the Icelandic community for all good times and laughter through the years. It’s really good to know that you are out there!
Parents in law Ransý and Guðmundur and family in law for being the nice and warm hearted people you are.
All my au-pairs through the years – how had I managed without you!
My sister Ragnhildur and brothers Yngvi Kristinn and Benedikt with families. My little sister where would I be without you? You are the most honest, loving and caring person I know. You are my greatest supporter and wisest advisor. Thank you!
My loving parents Jón and Kristrún for making me believe that everything is possible as long as you really want it. That you can make things happen as long as you believe in yourself. For supporting me and believing in me in every situation.
My adoring family, my children Jón, Tómas, Karl, Guðmundur and Kristrún Ragnhildur for being so wonderful and making my life so perfect. My husband Hörður for taking care of things.
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