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Rheumatoid arthritis
Concise report
Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry
  1. J H Salmon1,
  2. P Cacoub2,
  3. B Combe3,
  4. J Sibilia4,
  5. B Pallot-Prades5,
  6. O Fain6,
  7. A Cantagrel7,
  8. M Dougados8,
  9. E Andres9,
  10. O Meyer10,
  11. P Carli11,
  12. E Pertuiset12,
  13. I Pane13,
  14. F Maurier14,
  15. P Ravaud13,
  16. X Mariette15 and
  17. J E Gottenberg16
  18. on behalf of all the investigators of AIR registry, the French Society of Rheumatology and the Club Rhumatismes et Inflammations
  1. 1Rheumatology Department, CHU Reims, Reims, France
  2. 2Departement Hospitalo-Universitaire I2B, UPMC Univ Paris 06, CNRS, UMR 7211, INSERM, UMR_S 959, Department of Internal Medicine, Groupe Hospitalier Pitié-Salpêtrière (AP-HP), Paris, France
  3. 3Rheumatology Department, Lapeyronie University Hospital, Montpellier I, University, UMR5535, Montpellier, France
  4. 4Rheumatology department, National Center for Rare Systemic Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, INSERM UMRS_1109, Université de Strasbourg, Strasbourg, France
  5. 5Rheumatology Department, CHU Saint-Etienne, Saint-Etienne, France
  6. 6Department of Internal Medicine, Hôpital Jean Verdier, Bondy, France
  7. 7Rheumatology Center, Purpan Hospital, Paul Sabatier University, Toulouse, France
  8. 8Medicine Faculty, Paris-Descartes University, Paris, UPRES-EA 4058, Cochin Hospital, Rheumatology B, Paris, France
  9. 9Department of Internal Medicine, University Hospital of Strasbourg, Strasbourg, France
  10. 10Rheumatology Department, GroupeHospitalier Bichat-Claude Bernard (AP-HP), Paris, France
  11. 11Department of Internal Medicine, Hôpital D'Instruction des Armeés Sainte-541 Anne, Toulon, France
  12. 12Rheumatology Department, CH René Dubos, Pontoise, France
  13. 13Centre de Recherche en Epidémiologie et Statistiques, INSERM U1153, Centre d'Épidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris (AP-HP), Descartes University, Paris, France
  14. 14Department of Internal Medicine, CHR Metz, Metz, France
  15. 15Rheumatology Department, Hôpitaux Universitaires Paris-Sud, AP-HP, INSERM U1184, IMVA: Center of Immunology of Viral Infections and Autoimmune Diseases, Paris, France
  16. 16Rheumatology Department, National Center for Rare Systemic Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, CNRS, Institut de Biologie Moléculaire et Cellulaire, Immunopathologie et Chimie Thérapeutique/Laboratory of Excellence Medalis, Université de Strasbourg, Strasbourg, France
  1. Correspondence to Professor Jacques-Eric Gottenberg; jacques-eric.gottenberg{at}chru-strasbourg.fr

Abstract

Objectives To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry.

Methods The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient.

Results Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm3, 8 (20%) had neutrophils between 500 and 1000/mm3, and 26 (65%) had neutrophils between 1000 and 1500/mm3. Neutropenia occurred after a median period of 4.5 (3–6.5) months after the last RTX infusion in patients with RA, and 5 (3–6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm3, developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them.

Conclusions Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs.

  • Rheumatoid Arthritis
  • Autoimmune Diseases
  • Treatment

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/rmdopen-2014-000034

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    Key messages

    What is already known about this subject?

    • Late-onset neutropenia rituximab was mainly reported in patients treated for lymphoma but data in patients with rheumatoid arthritis and other AIDs are very limited.

    What does this study add?

    • The incidence of LON is much lower in RA and other AIDs than in blood malignancies. Neutropenia is usually mild and might not be complicated with infections.

    How might this impact on clinical practice?

    • Instead of monitoring whole blood count after each cycle of RTX, a more pragmatic approach could be to have a blood count performed in the event of fever or infection in the months following RTX treatment.

    Introduction

    Late-onset neutropenia (LON) after B-cell depletion by rituximab (RTX) was mainly reported in patients treated for lymphoma with an observed prevalence of 8%.1 LON can occur from 1 month up to 1 year after RTX.2 The mechanism of this complication remains poorly understood. Several assumptions exist regarding the pathogenesis of neutropenia after RTX in B-cell lymphoma, including the role of antineutrophil antibodies, large granular lymphocytes, competition for growth factors between lymphopoiesis and granulopoiesis,3–7 and the role of genetic polymorphisms in the immunoglobulin G (IgG) receptor FCγ RIIIA.8 ,9 The upregulation of B-cell activating factor of the tumour necrosis factor (TNF) family (BAFF) after B-cell depletion might also play a role by favouring B-cell repopulation to the detriment of granulopoiesis.3 The pathogenesis and concomitant treatments are very different between autoimmune diseases (AIDs) and lymphomas, which are usually treated with associated chemotherapy. Data on LON in patients with rheumatoid arthritis (RA) and other AIDs are very limited.10–15 One series of patients included 209 patients (162 RA and 47 AIDs, including 15 with systemic lupus erythematosus (SLE), 13 with granulomatosis with polyangiitis (GPA), 6 with juvenile RA and 13 with other AIDs), among whom 11 (5.2%: 5 RA and 6 AIDs) developed neutropenia.10 Recently, a retrospective series of 108 patients with RA reported 5 LON, of whom 2 developed infection.15 The aim of the present study was to evaluate the prevalence of LON and its complications in a large prospective cohort of patients treated with RTX for AIDs.

    Methods

    The French Society of Rheumatology and the Club Rhumatismeet Inflammations have set up the AutoImmunity and Rituximab (AIR) registry. The AIR registry is a multicentre prospective cohort designed to study the safety and efficacy of RTX in the treatment of RA and other refractory AIDs. Follow-up data are collected every 6 months over 7 years. Serious adverse events, including serious infections (requiring hospitalisation and/or intravenous antibiotics), cancers and deaths, are validated by the two coordinators of the registry using chart copies.

    The methodology of the registry was reported previously.16 ,17 This study was approved by the French authorities Comité Consultatif sur le Traitement de l'information en matière de Recherche dans le domaine de la Santé and Commission Nationale de l'Informatique et des Libertés. Written informed consent was obtained from all patients. Neutropenia is defined by an absolute blood neutrophil count less than 1500/mm3. Neutrophil count was requested at inclusion and at each follow-up visit (3 months, 6 months then every 6 months, or at any time in case of treatment change). Late-onset RTX-related neutropenia was defined as an absolute neutrophil count of ≤1.5×109/L starting from 4 weeks after termination of RTX therapy until 12 months after the last RTX infusion.2 Neutropenia prior to RTX and other drug-related neutropenia were excluded. At each visit, the crf includes specific questions regarding the potential complications of neutropenia. For each episode of neutropenia, data were abstracted from the electronic crf, validated and completed if necessary, using a specific questionnaire, by the clinician in charge of the patient.

    Statistical analysis

    Patients contributed person-years of follow-up between the first infusion of the first cycle and death, or the last follow-up visit. For the incidence rate calculation of neutropenia, the time of neutropenia was used as the right censoring rule. Rates of neutropenia are presented as event/100 patient-years. Data are presented as median (IQR) for quantitative values and proportions for qualitative values. All analyses were performed using SAS software V.9.3 (SAS system SAS Institute, Cary, North Carolina, USA). In univariate analysis, a χ2 test or Fisher's exact test was used for qualitative data according to application requirements. A non-parametric Mann-Whitney U test was used for quantitative values. A p value <0.05 was defined as significant.

    Results

    Characteristics of patients with neutropenia

    At the time of analysis, 2624 patients had at least one follow-up visit, including 1975 patients with RA and 649 patients with other AIDs. The median follow-up of patients with RA was 24.2 months (14.7–35.3) (4179 patient-years) and that of patients with AIDs was 17.4 months (5.6–29.1) (987 patient-years). The median follow-up after the last regimen of RTX was 14.4 months (7.1–27.8) in RA and 18.6 months (8.5–31.8) in AIDs. The median (IQR) number of blood counts was 4 (3–6) for patients with RA. The median (IQR) interval between blood counts was 5.2 (4.1–6.7) months for patients with RA. The median (IQR) number of blood counts/cycles of RTX was 2 (1.4–3) for patients with RA. Neutropenia was reported in 85 patients (48 RA and 37 AIDs). Forty-five patients were excluded since they actually had neutropenia prior to RTX (n=22, including dysmyelopoiesis (n=3), Felty's syndrome (n=1), cyclic neutropenia (n=1), autoimmune neutropenia (n=1), no specific diagnosis (n=16)), had other drug-related neutropenia (n=8, including interferon treatment for hepatitis C virus infection (n=7), chemotherapy for lymphoma (n=1) or had normal neutrophil counts within 1 year after RTX infusions and one occurrence of neutropenia more than 1 year after RTX infusions (n=15) (figure 1). For the remaining 40 patients, including 25 RA (1.3% of patients, 0.6/100 patient-years) and 15 AIDs (2.3%, 1.5/100 patient-years), 7 SLE, 7 vasculitis (including 6 cryoglobulinemia-related vasculitis and 1 GPA and 1 myositis), no other cause of neutropenia but RTX was identified by the clinician. The characteristics of these 40 patients (37 women, 3 men) with LON are summarised in table 1.

    View this table:
    Table 1

    Characteristics of the 40 patients who developed rituximab-related neutropenia

    Figure 1
    Figure 1

    Flow chart of the study (AIDs, autoimmune diseases; RA, rheumatoid arthritis; RTX, rituximab).

    Characteristics of late-onset neutropenia

    Six patients (1 RA (0.05% of patients with RA, 0.02/100 patient-years) and 5 AIDs (0.7% of patients with AIDs, 0.5/100 patient-years)) had neutrophils <500/mm3, 8 (7 RA and 1 AIDs) had neutrophils between 500 and 1000/mm3 neutrophils, and 26 (17 RA and 9 AIDs) had neutrophils between 1000 and 1500/mm3.

    Neutropenia occurred after a median period of 4.5 (3–6.5) months after the last infusion of RTX in patients with RA and 5 (3–6.5) months in patients with AIDs. In patients with RA, neutropenia occurred after the first cycle in 2 patients, after the second cycle in 4 patients, after the third cycle in 7 patients with RA and after the fourth cycle or later in 12 patients. In patients with AIDs, neutropenia occurred after the first cycle in 9 patients, after the second cycle in 5 patients and after the fourth cycle in 1 patient. Numerous episodes of neutropenia occurred after the second or subsequent cycle of RTX (92% in RA and 44% in AIDs). They were mainly mild neutropenia (blood neutrophil count between 1000 and 1500/mm3 in 17 RA and 2 AIDs; between 500 and 1000/mm3 in 6 RA and 1 AIDs; 3 AIDs had neutrophils <500/mm3).

    Five patients (1 RA and 4 AIDs) (12.5% of patients with neutropenia), four of them with neutrophils lower than 500/mm3, developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor (G-CSF) injections, with a favourable outcome. These episodes of neutropenia occurred after the first cycle for 2 patients, after the second cycle for 2 patients and after the fourth cycle for 1 patient. No patient had an opportunistic infection (table 2). In all patients, the outcome was favourable after treatment.

    View this table:
    Table 2

    Characteristics of the five patients treated with antibiotics and growth factors

    Associated factors with LON in RA

    Among the baseline characteristics of patients with RA, including gender, disease duration, RF and anti-cyclic citrullinated peptide activity, the number of previous synthetic disease-modifying antirheumatic drugs (DMARDs), number of previous anti-TNF, disease activities at enrolment, concomitant treatment with DMARD or corticosteroids, serum gammaglobulin and IgG levels, only female gender and age were associated with neutropenia (table 3).

    View this table:
    Table 3

    Associated factors with LON in RA

    Re-treatment with RTX

    Nineteen patients (47.5%) with previous neutropenia after RTX received a new infusion of RTX after resolution of their neutropenia (13 patients with RA with a previous blood neutrophil count between 1000 and 1500/mm3, four patients with RA between 500 and 1000/mm3, and two patients with SLE between 1000 and 1500/mm3). In the patients re-treated with RTX, the median number of cycles was 3 (2–4) in RA and 2 (2–2) in AIDs. The median follow-up of the re-treated patients was 26.1 months (21.8–39.2) in RA and 25.2 months (19.6–30.8) in AIDs. Neutropenia reoccurred in three of them (blood neutrophil count between 1000 and 1500/mm3 in two, and between 500 and 1000/mm3 in one). None of these recurrent episodes of neutropenia required growth factors or was complicated by an infection.

    Discussion

    The occurrence of late-onset neutropenia after RTX was infrequent in a large prospective registry, and the related complications were moderately severe. However, the rate of late-onset neutropenia after RTX in patients with RA and other AIDs has not been clearly determined. The AIR registry was very well adapted to this purpose since the occurrence of neutropenia and the blood neutrophil count were specifically requested in the e-crf at each follow-up visit. In addition, data validation by the clinician allowed us to identify patients with neutropenia unrelated to RTX. However, the main limitations of the study are related to its observational design, and missing data, notably duration of neutropenia that was not requested by the crf.

    The first important result of this study is the low rate of late-onset neutropenia after RTX in RA (1.3% of patients, 0.6/100 patient-years) and other AIDs (2.3%, 1.5/100 patient-years) in a large multicentre registry of unselected patients. The rate observed in this study is much lower than in the few previous reports concerning AIDs.10–12 Despite the observational setting of this registry study, patients had regular assessments of neutrophil counts approximately every 6 months. However, asymptomatic LON can occur in between blood tests. Thus, it cannot be ruled out that the higher frequency of neutropenia after RTX in patients with haematological malignancies could also be partly related to the more frequent follow-up of blood counts by haematologists than by rheumatologists. Therefore, the actual frequency of LON in this study might be underestimated as reported in lymphomas.18

    In our study, the mean time of onset of neutropenia was approximately 5 months, in accordance with what has been observed in this previous studies in AIDs and in lymphoma (around 6 months1–3), confirming their known late onset. No risk factor of neutropenia could be identified among the baseline characteristics of patients with RA, except age and female gender. Concerning gender, this may be simply due to the significantly higher prevalence of AIDs in women. Of note, lymphoma gender-based differences in RTX clearance were reported in elderly (>70 years) female patients treated with RTX for diffuse large B-cell lymphomas.19 The large numeric disequilibrium between 25 patients with RA with neutropenia and over 1900 patients without neutropenia inevitably led to a flawed statistical analysis due to type 2 errors.

    The second important result was the low number of complications associated with neutropenia after RTX. First, most of the LONs were mild (>500/mm3), and only a minority of the patients who had a very low blood neutrophil count required growth factors and antibiotics. Among the five patients who required growth factors and antibiotics, two had concomitant cyclophosphamide and were not treated with a concomitant immunosuppressant other than RTX. Concordantly, a previous report also showed that complications usually concern patients with a very low blood neutrophil count.3 However, the overall rate of infections was higher in that previous report than in this study, which might be related to a different distribution of AIDs. No opportunistic infection or death was related to neutropenia. Thus, late-onset neutropenia does not seem to increase the risk for serious infection as much as RTX-related hypogammaglobulinemia.13 ,20 The absence of clinical consequences of most of these neutropenias might explain that more than half of the patients with RA with a history of previous RTX-induced mild neutropenia were subsequently re-treated with RTX. However, data regarding the risk of reoccurrence of neutropenia after re-treatment with RTX are not available in the literature. Interestingly, in this study, a recurrent episode of uncomplicated neutropenia was observed in only 16% of re-treated patients, with only one patient having a blood neutrophil count below 1000/mm3. However, no firm conclusions can be drawn about RTX re-treatment of patients with previous LON, since there was a selection bias in patients who were re-treated, all of whom had previously experienced only mild neutropenia.

    Conclusion

    Late-onset neutropenia might occur after RTX in patients with RA and other AIDs, but its incidence is much lower than in patients with blood malignancies. In addition, late-onset neutropenia is usually mild and might not be complicated with infections. Regarding clinical practice, it has been recommended to monitor whole blood count after each cycle of RTX.21 Since late-onset neutropenia is not frequent, not predictable and of varying onset and duration, and since it rarely results in significant infection, a more pragmatic approach could be to have a blood count performed in the event of fever or infection in the months following RTX treatment.

    Acknowledgments

    Roche provided an unrestricted educational grant to the French Society of Rheumatology but was not involved in the design, protocol, data collection or statistical analysis of the study. The authors thank all the investigators who have included patients in the AIR registry, the French Society of Rheumatology (SFR), the Club Rhumatismes et Inflammation, the French National Society of Internal Medicine (SNFMI) for their implication in the AIR registry, Rosemary Jourdan (Roche), Jamila Filipecki and Nadine Mackenzie (formerly Roche). They also thank the 14 research study nurses (A Bourgeois, E Braychenko, F Carmet, MH Da Silva, S Delmas, D Guinement, R Lefebure, C Lehning, N Minot, FMA Ouattara, V Pinosa, M Reau, H Thibault and E Wallet), L Dongmo and V Martin, all working in Euraxipharma, the contract research organisation in charge of data collection in the AIR registry.

    References

    1. ↵
      1. Dunleavy K,
      2. Tay K,
      3. Wilson WH
      . Rituximab-associated neutropenia. Semin Hematol 2010;47:180–6. doi:10.1053/j.seminhematol.2010.01.009
      OpenUrlCrossRefPubMed
    2. ↵
      1. Buch MH,
      2. Smolen JS,
      3. Betteridge N, et al
      . Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:909–20. doi:10.1136/ard.2010.144998
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Terrier B,
      2. Ittah M,
      3. Tourneur L, et al
      . Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery. Haematologica 2007;92:20–3. doi:10.3324/haematol.11031
      OpenUrlCrossRef
    4. ↵
      1. Voog E,
      2. Morschhauser F,
      3. Solal-Celigny P
      . Neutropenia in patients treated with rituximab. N Engl J Med 2003;348:2691–4. doi:10.1056/NEJM200306263482620
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Papadaki T,
      2. Stamatopoulos K,
      3. Stavroyianni N, et al
      . Evidence for T-large granular lymphocyte-mediated neutropenia in Rituximab-treated lymphoma patients: report of two cases. Leuk Res 2002;26:597–600. doi:10.1016/S0145-2126(01)00183-7
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Papadaki T,
      2. Stamatopoulos K,
      3. Anagnostopoulos A, et al
      . Rituximab-associated immune myelopathy. Blood 2003;102:1557–8. doi:10.1182/blood-2003-05-1532
      OpenUrlFREE Full Text
    7. ↵
      1. Ma Q,
      2. Jones D,
      3. Springer TA
      . The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999;10:463–71. doi:10.1016/S1074-7613(00)80046-1
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Weng WK,
      2. Negrin RS,
      3. Lavori P, et al
      . Immunoglobulin G Fc receptor FcgammaRIIIa 158V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin's lymphoma. J Clin Oncol 2010;28:279–84. doi:10.1200/JCO.2009.25.0274
      OpenUrlAbstract/FREE Full Text
    9. ↵
      1. Li SC,
      2. Chen YC,
      3. Evens AM, et al
      . Rituximab-induced late-onset neutropenia in newly diagnosed B-cell lymphoma correlates with Fc receptor FcgammaRIIIa 158(V/F) polymorphism. Am J Hematol 2010;85:810–12. doi:10.1002/ajh.21818
      OpenUrlCrossRefPubMed
    10. ↵
      1. Tesfa D,
      2. Ajeganova S,
      3. Hagglund H, et al
      . Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum 2011;63:2209–14. doi:10.1002/art.30427
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Goh MS,
      2. McCormack C,
      3. Dinh HV, et al
      . Rituximab in the adjuvant treatment of pemphigus vulgaris: a prospective open-label pilot study in five patients. Br J Dermatol 2007;156:990–6. doi:10.1111/j.1365-2133.2007.07800.x
      OpenUrlCrossRefPubMed
    12. ↵
      1. Rios-Fernandez R,
      2. Gutierrez-Salmeron MT,
      3. Callejas-Rubio JL, et al
      . Late-onset neutropenia following rituximab treatment in patients with autoimmune diseases. Br J Dermatol 2007;157:1271–3. doi:10.1111/j.1365-2133.2007.08189.x
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Besada E,
      2. Koldingsnes W,
      3. Nossent J
      . Characteristics of late onset neutropenia in rheumatologic patients treated with rituximab: a case review analysis from a single center. QJM 2012;105:545–50. doi:10.1093/qjmed/hcs015
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Besada E
      . Alternative explanations for development of late-onset neutropenia in rituximab-treated rheumatic disease patients: comment on the article by Tesfa et al. Arthritis Rheum 2012;64:596–7. doi:10.1002/art.33428
      OpenUrlCrossRefPubMed
    15. ↵
      1. Abdulkader R,
      2. Dharmapalaiah C,
      3. Rose G, et al
      . Late-onset neutropenia in patients with rheumatoid arthritis after treatment with rituximab. J Rheumatol 2014;41:858–61. doi:10.3899/jrheum.130526
      OpenUrlAbstract/FREE Full Text
    16. ↵
      1. Mariette X,
      2. Gottenberg JE,
      3. Ravaud P, et al
      . Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries. Rheumatology (Oxford) 2011;50:222–9. doi:10.1093/rheumatology/keq368
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Gottenberg JE,
      2. Ravaud P,
      3. Bardin T, et al
      . Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010;62:2625–32. doi:10.1002/art.27555
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Cattaneo C,
      2. Spedini P,
      3. Casari S et al
      . Delayed-onset peripheral blood cytopenia after rituximab: frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 2006;47:1013–17. doi:10.1080/10428190500473113
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Pfreundschuh M,
      2. Muller C,
      3. Zeynalova S, et al
      . Suboptimal dosing of rituximab in male and female patients with DLBCL. Blood 2014;123:640–6. doi:10.1182/blood-2013-07-517037
      OpenUrlAbstract/FREE Full Text
    20. ↵
      1. van Vollenhoven RF,
      2. Emery P,
      3. Bingham CO, III., et al
      . Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013;72:1496–502. doi:10.1136/annrheumdis-2012-201956
      OpenUrlAbstract/FREE Full Text
    21. ↵
      1. Pham T,
      2. Fautrel B,
      3. Gottenberg JE, et al
      . Rituximab (MabThera) therapy and safety management. Clinical tool guide. Joint Bone Spine 2008;75(Suppl 1):S1–99. doi:10.1016/j.jbspin.2008.09.003
      OpenUrlPubMedWeb of Science

    Footnotes

    • Contributors All the authors contributed to data collection, interpretation of results and edited the manuscript. IP and PR performed statistical analyses. JHS, JEG and XM initiated the study and wrote the manuscript.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Comité Consultatif sur le Traitement de l'information en matière de Recherche dans le domaine de la Santé.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement No additional data are available.