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Tolerability and Safety of Long-Term Rituximab Treatment in Systemic Infammatory and Autoimmune Diseases

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Tolerability and Safety of Long-Term Rituximab Treatment in Systemic Infammatory and Autoimmune Diseases Rheumatology International (2019) 39:1083–1090 Rheumatology https://doi.org/10.1007/s00296-019-04272-1 INTERNATIONAL PHARMACOVIGILANCE Tolerability and safety of long-term rituximab treatment in systemic infammatory and autoimmune diseases Jens Vikse1 · Kristin Jonsdottir2 · Jan Terje Kvaløy2,3 · Klaus Wildhagen1 · Roald Omdal1,4 Received: 28 January 2019 / Accepted: 2 March 2019 / Published online: 28 March 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic infammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30–138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren’s syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the frst 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observa- tional data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side efects were observed. Keywords Rituximab · B-cell depletion · Immunosuppression · Safety · Tolerance Introduction * Roald Omdal [email protected] Jens Vikse Rituximab is a chimeric anti-CD20 monoclonal antibody [email protected] which causes selective B-cell depletion through a variety Kristin Jonsdottir of antibody-, cell- and complement-mediated mechanisms [email protected] [1]. While initially introduced as an antineoplastic agent, Jan Terje Kvaløy rituximab-mediated B-cell depletion became a promising [email protected] therapeutic option in B-cell-driven systemic infammatory Klaus Wildhagen and autoimmune diseases (SIADs) at the beginning of the [email protected] new millennium. Rituximab is now approved for treatment of rheumatoid arthritis (RA), granulomatosis with poly- 1 Clinical Immunology Unit, Stavanger University Hospital, angiitis (GPA) and microscopic polyangiitis (MPA), and is Stavanger, Norway frequently used as of-label therapy for a wide variety of 2 Research Department, Stavanger University Hospital, other SIADs when conventional treatment regimens have Stavanger, Norway failed [1–8]. Clinical trials in systemic lupus erythematosus 3 Department of Mathematics and Physics, University (SLE) and primary Sjögren’s syndrome (pSS) have been of Stavanger, Stavanger, Norway disappointing [9–11], but it has been argued that the instru- 4 Department of Clinical Science, Faculty of Medicine, ments used to monitor disease activity and remission have University of Bergen, Bergen, Norway Vol.:(0123456789)1 3 1084 Rheumatology International (2019) 39:1083–1090 not been sufciently sensitive to detect the clinical and bio- and Transfusion Medicine, Haukeland University Hospital, logical efects of rituximab [7]. Furthermore, clinical experi- Bergen, Norway. ence and case reports indicate that rituximab has a favorable efect in some subjects, and of-label use has, therefore, been Data collection and measurements increasingly employed in patients that do not respond to con- ventional immunosuppressive treatment. The electronic medical records of all patients with SIADs Adverse events related to rituximab treatment include, treated with rituximab, either as monotherapy or in combina- among others, infections, infusion reactions, dysgamma- tion with other immunosuppressive agents, were reviewed. globulinemia and cytopenia. Infammatory end organ dam- Data regarding gender, indication for rituximab, age at start age, such as interstitial pneumonitis and pyoderma gan- of treatment, as well as prior and current immunosuppres- grenosum are recognized as late-onset complications [12, sive therapy were systematically collected. Results of routine 13]. Nevertheless, previous studies have demonstrated that blood tests, as well as treatment complications were thor- long-term rituximab treatment in various SIADs is relatively oughly registered. Treatment complications included dys- well tolerated [14–18]. gammaglobulinemia (defned as subnormal levels of one or During the last 15 years, the Clinical Immunology Unit two of the three major serum immunoglobulin subclasses, at Stavanger University Hospital have employed rituximab IgG, IgA and IgM, and/or need for immunoglobulin sub- in more than 100 patients with difcult to treat SIADs. As stitution to maintain normal levels), hypogammaglobuline- several of these patients have received continuous rituxi- mia (defned as subnormal levels of all three major serum mab treatment for more than 10 years, this experience can immunoglobulin subclasses), infection (defned as a condi- provide additional insight into the tolerability and conse- tion requiring hospitalization with a presumed or confrmed quences of long-term therapeutic B-cell depletion. The aim infectious etiology and/or clinical response to antimicrobial of this retrospective study was, therefore, to evaluate the treatment) and end organ damage (defned as a presumed long-term safety and tolerance of rituximab, with special non-infectious infammatory process necessitating hospi- attention to dysgammaglobulinemia, infections, and failure talization which could not be attributed to activity of the of B-cell reconstitution following discontinuation of rituxi- underlying infammatory condition). Persistent dysgam- mab treatment. Due to the retrospective nature of the design, maglobulinemia was defned as dysgammaglobulinemia for this study did not intend to evaluate treatment efcacy. two consecutive measurements and persisting throughout the duration of rituximab therapy. Cytopenia was defned as subnormal levels of leukocytes, neutrophils or thrombocytes for two consecutive measurements and persisting throughout Materials and methods the treatment duration. Days of hospitalization, as well as need for admission to an intensive care unit and mechanical Study design ventilation was noted for all complications requiring hospital admission. Rituximab treatment duration, number of infu- This was a single-center, retrospective observational study sions, as well as reasons for discontinuation of rituximab which included all patients ≥ 16 years treated with rituximab were noted. In patients who had discontinued rituximab, for SIADs at Stavanger University Hospital between 2003 data concerning immunoglobulins and CD19 + B-cells in and 2017. Only patients receiving rituximab for a minimum the post-treatment period were collected to evaluate time to duration of ≥ 2 years were included. Patients with coexisting B-cell reconstitution. malignancies were excluded. Regardless of indication, all patients received an identical and standard treatment regi- Participants men consisting of two intravenous infusions of 1000 mg rituximab with two weeks interval at the start of treatment, One hundred patients were identifed, of which 25 were followed by 1000 mg every 6 months, as per institution excluded due to treatment duration of < 2 years, and 5 protocol. A standard pretreatment regimen consisting of were excluded due to coexisting malignancies. No patients paracetamol, diphenhydramine, and methylprednisolone were lost to follow-up and no patients declined inclu- was given to limit infusion reactions. Prior to each infu- sion, leaving a total sample size of 70 patients for inclu- sion, routine blood tests were obtained, including complete sion. There was a slight female predominance (58.6% vs. blood count, levels of immunoglobulins and immunopheno- 41.4%), and the median age at initiation of rituximab treat- typing of lymphocytes for quantitation of CD19 + B-cells in ment was 51.5 years (IQR 21.3), ranging 16–81 years. The peripheral blood. Routine biochemical and immunological specifc diseases and conditions for which rituximab was analyses were performed at Stavanger University Hospital, given were diverse, with GPA, pSS and SLE being the and immunophenotyping at the Department of Immunology most common (Table 1). Three patients (4.3%) received 1 3 Rheumatology International (2019) 39:1083–1090 1085 Table 1 Indication for Diagnosis Number of rituximab treatment patients (%) Granulomatosis with polyangiitis 16 (22.9%) Primary Sjögren’s syndrome 14 (20.0%) Systemic lupus erythematosus 10 (14.3%) Rheumatoid arthritis 5 (7.1%) Eosinophilic granulomatosis with polyangiitis
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