An unexpected response to rituximab in a patient with rheumatoid arthritis

An unexpected response to rituximab in a patient with rheumatoid arthritis Rheumatology key message Permanent blockade of CD19+ CD20+ B cell generation in rheumatoid arthritis is associated with long-term remission. Sir, Rituximab, a chimeric mAb that selectively targets CD20+ B cells, induces clinical remission in most seropositive patients with RA. However, patients inevitably relapse following infusions, mostly within the next 6–12 months [1]. We report herein the case of a patient with a 9-year history of sustained biologic-free clinical remission, along with persistent peripheral B cell depletion, after three iterative rituximab courses. Prior to the first rituximab cure in 2006, the 54-year-old patient had been suffering from a severely active RA since 1992, along with pulmonary fibrosis, having not responded to conventional therapy. Etanercept was initiated in 2004 though discontinued in 2005, owing to worsening of the pulmonary fibrosis. In March 2006, two infusions of rituximab 1000 mg were administered to the patient with a 2-week interval. At this time, his disease was clinically and serologically very active (Fig. 1A and B). In the months after treatment, a significant clinical improvement was observed, with the disease remaining stable for 9 months then requiring a second rituximab course (2 × 1000 mg, 2 weeks apart). Once again, disease relapse occurred 1 year thereafter, requiring the patient to be re-treated with rituximab (2 × 1000 mg, 2 weeks apart). Since this second rituximab treatment delivered in 2008, the patient has not experienced any clinical relapse, the disease remaining quiescent without any biologic treatment given. During the 9-year follow-up, peripheral CD19+ B cells were undetectable (Fig. 1C) and levels of both anti-CCP antibodies and immunoglobulins G declined (Fig. 1B and D) yet the decline in anti-CCP antibodies occurred at a more rapid rate. Despite these immunological abnormalities, the patient has not experienced any severe infection since the last rituximab cure over the 9-year follow-up. Fig. 1 View largeDownload slide Clinical and laboratory parameters over time after rituximab treatment (A) DAS28 after rituximab (RTX) courses. (B) Anti-CCP antibodies and RF concentrations. (C) Percentages of peripheral lymphocytes (determined by flow cytometry, after acquisition of 10 000 CD45+ cells. B cells were gated as CD45+ CD20+ cells representing <1 cell/µl). (D) Immunoglobulins G concentrations. All sera were stored at − 80 °C and requantified extemporaneously using the same technique, to avoid measurement bias arising from technique changes over the 10 years of follow-up. Fig. 1 View largeDownload slide Clinical and laboratory parameters over time after rituximab treatment (A) DAS28 after rituximab (RTX) courses. (B) Anti-CCP antibodies and RF concentrations. (C) Percentages of peripheral lymphocytes (determined by flow cytometry, after acquisition of 10 000 CD45+ cells. B cells were gated as CD45+ CD20+ cells representing <1 cell/µl). (D) Immunoglobulins G concentrations. All sera were stored at − 80 °C and requantified extemporaneously using the same technique, to avoid measurement bias arising from technique changes over the 10 years of follow-up. To our knowledge, this case report is the biologic-free complete clinical remission of the longest duration documented after introducing biologic therapy in a patient with very advanced disease. Whether such sustained remission occurs more commonly after rituximab compared with other treatments is still unknown. However, identifying persistent remission is probably easier with rituximab, which is typically administered only during relapses, unlike other biotherapies administered at regular intervals, even in the absence of flare, thus rendering remission cases more difficult to identify. This case report nicely illustrates the critical involvement of B cells in disease progression, with these cells acting directly via the secretion of pathogenic autoantibodies and/or indirectly via the modulation of autoreactive T cells [2]. Interestingly, several aspects of this case merit further discussion. Firstly, our observation challenges the concept that biologic-free remission is unlikely to occur in patients with long-standing RA. According to the current paradigm, namely the window of opportunity concept, several RA patients may achieve biologic-free remission following early therapeutic intervention. This observation is based on the hypothesis that autoimmunity is not fully established during the early disease phase. As a result, long-lasting disease is supposedly associated with irreversible autoimmunity, presumed to be incompatible with long term biologic-free remission [3]. The corollary of this concept is that inducing long-term remission in advanced RA stages would necessitate a purge of autoimmune cells, an undemonstrated hypothesis to date. Secondly, it appears rather surprising that long-term B cell depletion is so well tolerated by our patient, given that he has never required immunoglobulin replacement therapy, unlike other patients with persistent post-rituximab B cell dysfunction [4, 5]. Despite B cell depletion, the patient has likely maintained the level of total immunoglobulins G, which has proven sufficiently high to protect him against infectious agents [6]. This maintenance of protective humoral immunity might be explained by the contribution of the recently described CD19− subset of plasma cells that contribute to long-lived protection against infection and do not require replenishment from CD20+ B cells [7, 8]. It is thus tempting to speculate that the CD19− long-lived plasma cell compartment of our patient contains the historical record of B cell responses mounted early in life, notably against pathogens, while being almost devoid of plasma cells activated later in life such as autoimmune plasma cells. Given this scenario, autoimmune plasma cells could be primarily restricted to the CD19+ plasma cell compartment that requires replenishment from CD20+ B cells. Permanent blockade of such cell generation by a hitherto unknown mechanism, as observed in our patient, may account for the unexpected long-term remission. Decrypting the mechanisms of medication-free remission at the cellular and molecular levels in patients such as this one might provide invaluable information on the pathogenic role of different B cell subsets in RA, thereby opening new therapeutic avenues. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Edwards JCW, Szczepański L, Szechiński J et al.   Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med  2004; 350: 2572– 81. Google Scholar CrossRef Search ADS PubMed  2 Panayi GS. B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology  2005; 44(Suppl 2): ii3– 7. Google Scholar CrossRef Search ADS PubMed  3 Nagy G, van Vollenhoven RF. Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Res Ther  2015; 17: 181. Google Scholar CrossRef Search ADS PubMed  4 Kaplan B, Kopyltsova Y, Khokhar A, Lam F, Bonagura V. Rituximab and immune deficiency: case series and review of the literature. J Allergy Clin Immunol Pract  2014; 2: 594– 600. Google Scholar CrossRef Search ADS PubMed  5 Barmettler S, Price C. Continuing IgG replacement therapy for hypogammaglobulinemia after rituximab—for how long? J Allergy Clin Immunol  2015; 136: 1407– 9. Google Scholar CrossRef Search ADS PubMed  6 van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB. Longterm safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years. J Rheumatol  2015; 42: 1761– 6. Google Scholar CrossRef Search ADS PubMed  7 Halliley JL, Tipton CM, Liesveld J et al.   Long-lived plasma cells are contained within the CD19−CD38hiCD138+ subset in human bone marrow. Immunity  2015; 43: 132– 45. Google Scholar CrossRef Search ADS PubMed  8 Mei HE, Wirries I, Frölich D et al.   A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood  2015; 125: 1739– 48. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

An unexpected response to rituximab in a patient with rheumatoid arthritis

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1462-0324
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1462-0332
D.O.I.
10.1093/rheumatology/kex418
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Abstract

Rheumatology key message Permanent blockade of CD19+ CD20+ B cell generation in rheumatoid arthritis is associated with long-term remission. Sir, Rituximab, a chimeric mAb that selectively targets CD20+ B cells, induces clinical remission in most seropositive patients with RA. However, patients inevitably relapse following infusions, mostly within the next 6–12 months [1]. We report herein the case of a patient with a 9-year history of sustained biologic-free clinical remission, along with persistent peripheral B cell depletion, after three iterative rituximab courses. Prior to the first rituximab cure in 2006, the 54-year-old patient had been suffering from a severely active RA since 1992, along with pulmonary fibrosis, having not responded to conventional therapy. Etanercept was initiated in 2004 though discontinued in 2005, owing to worsening of the pulmonary fibrosis. In March 2006, two infusions of rituximab 1000 mg were administered to the patient with a 2-week interval. At this time, his disease was clinically and serologically very active (Fig. 1A and B). In the months after treatment, a significant clinical improvement was observed, with the disease remaining stable for 9 months then requiring a second rituximab course (2 × 1000 mg, 2 weeks apart). Once again, disease relapse occurred 1 year thereafter, requiring the patient to be re-treated with rituximab (2 × 1000 mg, 2 weeks apart). Since this second rituximab treatment delivered in 2008, the patient has not experienced any clinical relapse, the disease remaining quiescent without any biologic treatment given. During the 9-year follow-up, peripheral CD19+ B cells were undetectable (Fig. 1C) and levels of both anti-CCP antibodies and immunoglobulins G declined (Fig. 1B and D) yet the decline in anti-CCP antibodies occurred at a more rapid rate. Despite these immunological abnormalities, the patient has not experienced any severe infection since the last rituximab cure over the 9-year follow-up. Fig. 1 View largeDownload slide Clinical and laboratory parameters over time after rituximab treatment (A) DAS28 after rituximab (RTX) courses. (B) Anti-CCP antibodies and RF concentrations. (C) Percentages of peripheral lymphocytes (determined by flow cytometry, after acquisition of 10 000 CD45+ cells. B cells were gated as CD45+ CD20+ cells representing <1 cell/µl). (D) Immunoglobulins G concentrations. All sera were stored at − 80 °C and requantified extemporaneously using the same technique, to avoid measurement bias arising from technique changes over the 10 years of follow-up. Fig. 1 View largeDownload slide Clinical and laboratory parameters over time after rituximab treatment (A) DAS28 after rituximab (RTX) courses. (B) Anti-CCP antibodies and RF concentrations. (C) Percentages of peripheral lymphocytes (determined by flow cytometry, after acquisition of 10 000 CD45+ cells. B cells were gated as CD45+ CD20+ cells representing <1 cell/µl). (D) Immunoglobulins G concentrations. All sera were stored at − 80 °C and requantified extemporaneously using the same technique, to avoid measurement bias arising from technique changes over the 10 years of follow-up. To our knowledge, this case report is the biologic-free complete clinical remission of the longest duration documented after introducing biologic therapy in a patient with very advanced disease. Whether such sustained remission occurs more commonly after rituximab compared with other treatments is still unknown. However, identifying persistent remission is probably easier with rituximab, which is typically administered only during relapses, unlike other biotherapies administered at regular intervals, even in the absence of flare, thus rendering remission cases more difficult to identify. This case report nicely illustrates the critical involvement of B cells in disease progression, with these cells acting directly via the secretion of pathogenic autoantibodies and/or indirectly via the modulation of autoreactive T cells [2]. Interestingly, several aspects of this case merit further discussion. Firstly, our observation challenges the concept that biologic-free remission is unlikely to occur in patients with long-standing RA. According to the current paradigm, namely the window of opportunity concept, several RA patients may achieve biologic-free remission following early therapeutic intervention. This observation is based on the hypothesis that autoimmunity is not fully established during the early disease phase. As a result, long-lasting disease is supposedly associated with irreversible autoimmunity, presumed to be incompatible with long term biologic-free remission [3]. The corollary of this concept is that inducing long-term remission in advanced RA stages would necessitate a purge of autoimmune cells, an undemonstrated hypothesis to date. Secondly, it appears rather surprising that long-term B cell depletion is so well tolerated by our patient, given that he has never required immunoglobulin replacement therapy, unlike other patients with persistent post-rituximab B cell dysfunction [4, 5]. Despite B cell depletion, the patient has likely maintained the level of total immunoglobulins G, which has proven sufficiently high to protect him against infectious agents [6]. This maintenance of protective humoral immunity might be explained by the contribution of the recently described CD19− subset of plasma cells that contribute to long-lived protection against infection and do not require replenishment from CD20+ B cells [7, 8]. It is thus tempting to speculate that the CD19− long-lived plasma cell compartment of our patient contains the historical record of B cell responses mounted early in life, notably against pathogens, while being almost devoid of plasma cells activated later in life such as autoimmune plasma cells. Given this scenario, autoimmune plasma cells could be primarily restricted to the CD19+ plasma cell compartment that requires replenishment from CD20+ B cells. Permanent blockade of such cell generation by a hitherto unknown mechanism, as observed in our patient, may account for the unexpected long-term remission. Decrypting the mechanisms of medication-free remission at the cellular and molecular levels in patients such as this one might provide invaluable information on the pathogenic role of different B cell subsets in RA, thereby opening new therapeutic avenues. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Edwards JCW, Szczepański L, Szechiński J et al.   Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med  2004; 350: 2572– 81. Google Scholar CrossRef Search ADS PubMed  2 Panayi GS. B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? Rheumatology  2005; 44(Suppl 2): ii3– 7. Google Scholar CrossRef Search ADS PubMed  3 Nagy G, van Vollenhoven RF. Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Res Ther  2015; 17: 181. Google Scholar CrossRef Search ADS PubMed  4 Kaplan B, Kopyltsova Y, Khokhar A, Lam F, Bonagura V. Rituximab and immune deficiency: case series and review of the literature. J Allergy Clin Immunol Pract  2014; 2: 594– 600. Google Scholar CrossRef Search ADS PubMed  5 Barmettler S, Price C. Continuing IgG replacement therapy for hypogammaglobulinemia after rituximab—for how long? J Allergy Clin Immunol  2015; 136: 1407– 9. Google Scholar CrossRef Search ADS PubMed  6 van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB. Longterm safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years. J Rheumatol  2015; 42: 1761– 6. Google Scholar CrossRef Search ADS PubMed  7 Halliley JL, Tipton CM, Liesveld J et al.   Long-lived plasma cells are contained within the CD19−CD38hiCD138+ subset in human bone marrow. Immunity  2015; 43: 132– 45. Google Scholar CrossRef Search ADS PubMed  8 Mei HE, Wirries I, Frölich D et al.   A unique population of IgG-expressing plasma cells lacking CD19 is enriched in human bone marrow. Blood  2015; 125: 1739– 48. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

RheumatologyOxford University Press

Published: Mar 1, 2018

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