Factors Associated with Reduced Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Autoimmune Inflammatory Rheumatic Diseases (AIIRD) Treated with Rituximab

Victoria Furer¹, Tali Eviatar², Devy Zisman³, Hagit Peleg⁴, Daphna Paran⁵, David Levartovsky¹, Ilana Kaufman⁶, Michael Zisapel¹, Ofir Elalouf⁷, Roni Meidan¹, Adi Broyde⁸, Ari Polachek⁹, Jonathan Wollman⁷, Katya Meridor¹⁰, Hila Nochomovitz¹, Adi Silberman¹, Dana Rosenberg¹, Joy Feld¹¹, Amir Haddad¹², Tal Gazitt¹³, Muna Elias³, Nizar Hijaze¹⁴, Fadi Kharouf⁴, Gabi Shefer¹, Orly Sharon¹, Sara Pel¹, Sharon Nevo¹ and Ori Elkayam¹⁵, ¹Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, ²Tel Aviv Sourasky Medical Center, Givataim, Israel, ³Carmel Medical Center, Haifa, Israel, ⁴Hadassah Medical Center, Jerusalem, Israel, ⁵Tel Aviv Sourasky Medical Center-Ichilov Hospital, Even Yehuda, Israel, ⁶Tel Aviv Sourasky Medical Center, Petach Tiqwa, Israel, ⁷Tel Aviv Medical Center, Herzliya, Israel, ⁸Tel Aviv Sourasky Medical Center, KIBBUTZ GIVAT HAIM I, Israel, ⁹Sourasky Medical Center, Petah-Tikva, Israel, ¹⁰Tel Aviv Sourasky Medical Center, Kfar Saba, Israel, ¹¹Carmel and Zvulun Medical Centre, Haifa, Israel, ¹²Carmel Medical Centre, Haifa, Israel, ¹³Carmel Hospital, Haifa, Israel, ¹⁴Carmel medical centre, Tamra, Israel, ¹⁵Tel Aviv Medical Center, Tel Aviv, Israel

Meeting: ACR Convergence 2021

Keywords: ANCA associated vasculitis, autoimmune diseases, COVID-19, immunology

Session Information

Date: Saturday, November 6, 2021

Session Title: Abstracts: Immunological Complications of Therapy (0437–0440)

Session Type: Abstract Session

Session Time: 9:00AM-9:15AM

Background/Purpose: Rituximab (RTX) has been associated with impaired humoral response to vaccination. This study aim was to identify the predictors for a lack of humoral response to the BNT162b2 mRNA vaccine in patients with autoimmune inflammatory rheumatic diseases (AIIRD) treated with RTX.

Methods: We conducted a sub-analysis of the prospective multicenter study investigating immunogenicity of the two-dose regimen BNT162b2 mRNA vaccine in adult AIIRD patients, including rheumatoid arthritis (RA), systemic lupus erythematosus, systemic vasculitis, and inflammatory myositis treated with RTX compared to controls without rheumatic diseases or immunosuppressants use. Data on the serum IgG level prior to administration of the last course of RTX were collected. Post-vaccination serum IgG levels against SARS-CoV-2 spike S1/S2 proteins were measured 2 – 6 weeks after the 2^nd vaccine dose. Seropositivity was defined as IgG ³15 binding antibody units (BAU)/ml.

Statistical analysis included a stepwise backward multiple logistic regression for predicting a seropositive result on AIIRD patients with all data available (n=92), starting with all individual variables showing the significance level < 0.2 between seropositive and seronegative result.

Results: A total of 98 AIIRD patients (75.5% females) and 122 controls (64.8% females) were included in the study (table 1). AIIRD patients were significantly older vs controls, mean±standard deviation (SD) 62.3±14.6 vs 50.8±14.6 years, p>0.0001, respectively. Among AIIRD patients, 4 had a past history of lymphoma. Following vaccination, the seropositivity rate and S1/S2 IgG levels (mean±SD) were significantly lower among AIIRD patients vs controls, 38.8% (n=38) vs 100%, p < 0.0001 and 49.9±81 vs 218.4±81.2 BAU/ml, p < 0.0001, respectively.

Seronegative and seropositive AIIRD patients treated with RTX significantly differed by the total number of RTX courses, mean 5.9±4.0 vs 3.9±3.2, p=0.012; IgG levels prior to administration of the last course of RTX, 880.4±306.8 vs 1233±624 mg/dl, p=0.0036 and the interval between the last RTX course and vaccination, 158.3±157.9 vs 410.6±459.7 days, p=0.0019 (table 2). Multivariate logistic regression predicting a seropositive response to vaccination in patients treated with RTX showed that RA conferred the highest probability for a positive response, while ANCA-associated vasculitis conferred the lowest probability for a positive response. The odds ratio (OR) of ANCA associated vasculitis was marginally significant (OR = 0.223, p=0.059). Two other variables –IgG level prior the last course of RTX and interval (days) between the last RTX course and vaccination – were associated with a seropositive response: for every 1 mg/dl IgG increment – OR 1.002, 95%CI 1-1.004, p=0.013, and for every day increment – OR 1.007, 95%CI 1.003-1.001, p=0.002, respectively. (table 3)

Conclusion: In AIIRD patients treated with RTX, high exposure to RTX over time, low IgG levels prior to the last RTX course, and a short interval between the last RTX course and BNT162b2 vaccination predicted the absence of a humoral response to vaccination. These data should guide the optimal timing of vaccination in patients treated with RTX.

AIIRD, autoimmune inflammatory rheumatic disease; n, number; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; ANCA, antineutrophil cytoplasmic antibody; IIM, idiopathic inflammatory myopathies; IgG, immune globulin G; SD, standard deviation; DAS28, disease activity score 28; SLEDAI, systemic lupus erythematosus disease activity index; PGA, patient global assessment; PhGA, physician global assessment; VAS, visual analogue scale; RTX, rituximab; IVIG, intravenous immune globulin.

RTX-subanalysis_ACR_2021-Table_2.jpeg”

* Fisher exact test p-value for the comparison between the relevant diagnosis (RA, SLE, etc.) and all other diagnoses
AIIRD, autoimmune inflammatory rheumatic disease; n, number; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; ANCA, antineutrophil cytoplasmic antibody; IIM, idiopathic inflammatory myopathies; IgG, immune globulin G; SD, standard deviation; RTX, rituximab; IVIG, intravenous immune globulin.

* Original model included SLE, ANCA associated vasculitis, other systemic vasculitis, IIM, disease duration, serum IgG levels, cumulative rituximab dose, rituximab last course dose, total rituximab courses, and time interval between the last rituximab course and BNT162b2 vaccine.
Including and staying criterion was p < 0.2. RA was considered as a reference for diagnosis.

RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; ANCA, antineutrophil cytoplasmic antibody; IIM, idiopathic inflammatory myopathies; IgG, immune globulin G; RTX, rituximab.

Disclosures: V. Furer, None; T. Eviatar, None; D. Zisman, None; H. Peleg, None; D. Paran, None; D. Levartovsky, None; I. Kaufman, None; M. Zisapel, None; O. Elalouf, None; R. Meidan, None; A. Broyde, None; A. Polachek, None; J. Wollman, None; K. Meridor, None; H. Nochomovitz, None; A. Silberman, None; D. Rosenberg, None; J. Feld, None; A. Haddad, None; T. Gazitt, None; M. Elias, None; N. Hijaze, None; F. Kharouf, None; G. Shefer, None; O. Sharon, None; S. Pel, None; S. Nevo, None; O. Elkayam, NOVARTIS, 1, 2, 6, Pfizer, 1, 2, 5, 6, Lilly, 1, 2, 6, Abbvie, 1, 6, BI, 1, 6.

To cite this abstract in AMA style:

Furer V, Eviatar T, Zisman D, Peleg H, Paran D, Levartovsky D, Kaufman I, Zisapel M, Elalouf O, Meidan R, Broyde A, Polachek A, Wollman J, Meridor K, Nochomovitz H, Silberman A, Rosenberg D, Feld J, Haddad A, Gazitt T, Elias M, Hijaze N, Kharouf F, Shefer G, Sharon O, Pel S, Nevo S, Elkayam O. Factors Associated with Reduced Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Autoimmune Inflammatory Rheumatic Diseases (AIIRD) Treated with Rituximab [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/factors-associated-with-reduced-immunogenicity-of-the-bnt162b2-mrna-covid-19-vaccine-in-patients-with-autoimmune-inflammatory-rheumatic-diseases-aiird-treated-with-rituximab/. Accessed February 6, 2023.

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