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Research ArticleOther Arthritides
Open Access

Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases

Anne Troldborg, Marianne Kragh Thomsen, Lars Erik Bartels, Jakob Bøgh Andersen, Signe Risbøl Vils, Clara Elbæk Mistegaard, Anders Dahl Johannsen, Marie-Louise From Hermansen, Susan Mikkelsen, Christian Erikstrup, Ellen-Margrethe Hauge and Christian Ammitzbøll
The Journal of Rheumatology June 2022, 49 (6) 644-649; DOI: https://doi.org/10.3899/jrheum.211152
Anne Troldborg
1A. Troldborg, MD, PhD, Department of Rheumatology, Aarhus University Hospital, Department of Biomedicine, and Department of Clinical Medicine, Aarhus University;
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  • For correspondence: annetrol@rm.dk
Marianne Kragh Thomsen
2M.K. Thomsen, MD, Department of Clinical Medicine, Aarhus University, and Department of Clinical Microbiology, Aarhus University Hospital;
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Lars Erik Bartels
3L.E. Bartels, MD, PhD, J.B. Andersen, MD, A.D. Johannsen, MD, M.L.F. Hermansen, MD, PhD, Department of Rheumatology, Aarhus University Hospital;
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Jakob Bøgh Andersen
3L.E. Bartels, MD, PhD, J.B. Andersen, MD, A.D. Johannsen, MD, M.L.F. Hermansen, MD, PhD, Department of Rheumatology, Aarhus University Hospital;
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Signe Risbøl Vils
4S.R. Vils MS, Department of Rheumatology, Aarhus University Hospital, and Department of Biomedicine, Aarhus University;
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Clara Elbæk Mistegaard
5C.E. Mistegaard, MD, Department of Rheumatology, and Department of Clinical Microbiology, Aarhus University Hospital, and Department of Biomedicine, Aarhus University;
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Anders Dahl Johannsen
3L.E. Bartels, MD, PhD, J.B. Andersen, MD, A.D. Johannsen, MD, M.L.F. Hermansen, MD, PhD, Department of Rheumatology, Aarhus University Hospital;
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Marie-Louise From Hermansen
3L.E. Bartels, MD, PhD, J.B. Andersen, MD, A.D. Johannsen, MD, M.L.F. Hermansen, MD, PhD, Department of Rheumatology, Aarhus University Hospital;
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Susan Mikkelsen
6S. Mikkelsen, MD, Department of Clinical Immunology, Aarhus University Hospital;
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Christian Erikstrup
7C. Erikstrup, MD, PhD, Department of Clinical Medicine, Aarhus University, and Department of Clinical Immunology, Aarhus University Hospital;
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Ellen-Margrethe Hauge
8E.M. Hauge, MD, PhD, C. Ammitzbøll, MD, PhD, Department of Rheumatology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
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Christian Ammitzbøll
8E.M. Hauge, MD, PhD, C. Ammitzbøll, MD, PhD, Department of Rheumatology, Aarhus University Hospital, and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
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    Figure 1.

    Total SARS-CoV-2 antibody response after receiving 2 vaccinations with COVID-19 mRNA vaccine in patients with rheumatic diseases treated with RTX and controls. (A) Percentage of patients and controls with a measurable antibody response post vaccination. (B) Levels of measured total anti–SARS-CoV-2 antibodies in patients (circles) and controls (crosses). The X-axis shows time since the last treatment with rituximab prior to vaccination. COVID-19: coronavirus disease 2019; n: number of individuals with SARS-CoV-2 antibodies; N: total number of individuals; RTX: rituximab.

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    Table 1.

    Patient demographics (n = 201).

    Values
    Female sex135 (67)
    Age, yrs, mean (SD)58.4 (14.2)
    Previous COVID-19 infection7 (3.5)
    Disease duration, yrs, median (IQR)7.9 (3.0–8.0)
    Diagnosis
          Rheumatoid arthritis63 (31)
          Systemic lupus erythematosus20 (10)
          AAV (GPA/EGPA)61/4 (32)
          Polymyositis/dermatomyositis28 (14)
          Systemic sclerosis10 (5)
          Other RDs14 (7)
    mRNA vaccine used
          Pfizer/BioNTech195 (97)
          Moderna6 (3)
    Time from vaccination to blood sample, d, median (IQR)42 (12–64)
    DMARD treatment
          None52 (25)
          Prednisone84 (42)
              Prednisone dose, mg, median (IQR)5 (5–10)
          Methotrexate51 (25)
          Hydroxychloroquine22 (11)
          Azathioprine21 (10)
          Leflunomide11 (5)
          Mycophenolate mofetil9 (4)
          Ig6 (3)
          Cyclophosphamide2 (1)
          Sulfasalazine1 (0.5)
    Biologic treatment
          None35 (17)
          RTX within last 15 months145 (72)
          TNF inhibitors6 (3)
          JAK inhibitors6 (3)
          IL-6 inhibitors5 (2)
          Abatacept4 (2)
    Previous RTX treatment, median (IQR)
          No. of infusions5 (2–8)
          Cumulative total dose, mg4000 (2000–8000)
          Total treatment timea, d505 (30–1532)
    • Values are expressed as n (%) unless otherwise indicated.

    • ↵aTime between the first and last RTX treatment before vaccination. AAV: antineutrophil cytoplasmic antibody–associated vasculitis; COVID-19: coronavirus disease 2019; DMARD: disease-modifying antirheumatic drug; EGPA: eosinophilic granulomatosis with polyangiitis; GPA: granulomatosis with polyangiitis; IL: interleukin; JAK: Janus kinase; RD: rheumatic disease; RTX: rituximab; TNF: tumor necrosis factor.

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    Table 2.

    Univariate logistic regression analysis of antibody response after COVID-19 mRNA vaccination in patients.

    OR95% CIP
    Univariate logistic regression analysis
    Sex, female (ref)0.910.50–1.670.77
    Age, yrs0.980.96–1.000.09
    Time from vaccination to blood sample, days1.000.99–1.010.61
    Diagnosis
          Rheumatoid arthritisRefRefRef
          Systemic lupus erythematosus0.570.19–1.690.31
          AAV (GPA/EGPA)0.830.41–1.690.61
          Polymyositis/dermatomyositis0.360.13–1.020.06
          Systemic sclerosis1.330.35–5.070.67
          Other RDs2.670.82–8.710.10
    RTX exposure
          RTX treatment within last 15 months0.210.10–0.40< 0.001
          Time between last RTX and vaccination, months1.061.03–1.09< 0.001
          Total no. of RTX infusions0.960.92–1.010.10
          Total RTX dose, mg0.970.92–1.020.18
          Time from first to last RTX treatment, months1.001.00–1.000.57
    DMARD treatment
          None0.940.50–1.780.85
          Prednisone, yes/no (no = ref)0.490.27–0.890.02
              Prednisone dose, mg0.910.85–0.990.02
          Methotrexate1.710.90–3.250.10
          Hydroxychloroquine0.870.35–2.190.77
          Azathioprine0.230.06–0.800.02
    Multivariate logistic regression analysis
    Time between last RTX and vaccination, months1.081.04–1.11< 0.001
    DMARD treatment
          Prednisone dose, mg0.910.84–0.990.03
          Azathioprine0.100.02–0.440.002
    • Explanatory variables in the univariate model are based on previous knowledge of association to vaccination response and evaluation of RTX exposure. Specific DMARD treatments were included if ≥ 10% of the patients received it. The multivariate model includes all explanatory variables with statistically significant effects in the univariate analysis. “Time from last RTX treatment to vaccination” and “prednisone treatment” were included as continuous variables. Values in bold are statistically significant. AAV: antineutrophil cytoplasmic antibody–associated vasculitis; COVID-19: coronavirus disease 2019; DMARD: disease-modifying antirheumatic drug; EGPA: eosinophilic granulomatosis with polyangiitis; GPA: granulomatosis with polyangiitis; OR: odds ratio; RD: rheumatic disease; RTX: rituximab.

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The Journal of Rheumatology
Vol. 49, Issue 6
1 Jun 2022
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Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases
Anne Troldborg, Marianne Kragh Thomsen, Lars Erik Bartels, Jakob Bøgh Andersen, Signe Risbøl Vils, Clara Elbæk Mistegaard, Anders Dahl Johannsen, Marie-Louise From Hermansen, Susan Mikkelsen, Christian Erikstrup, Ellen-Margrethe Hauge, Christian Ammitzbøll
The Journal of Rheumatology Jun 2022, 49 (6) 644-649; DOI: 10.3899/jrheum.211152

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Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases
Anne Troldborg, Marianne Kragh Thomsen, Lars Erik Bartels, Jakob Bøgh Andersen, Signe Risbøl Vils, Clara Elbæk Mistegaard, Anders Dahl Johannsen, Marie-Louise From Hermansen, Susan Mikkelsen, Christian Erikstrup, Ellen-Margrethe Hauge, Christian Ammitzbøll
The Journal of Rheumatology Jun 2022, 49 (6) 644-649; DOI: 10.3899/jrheum.211152
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