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BackgroundComplete peripheral B cell depletion has been considered as a relevant indicator of short-term response to rituximab (RTX) in rheumatoid arthritis (RA) [1,2]. However, no information is available to validate this observation in RA patients long-term treated with RTX.ObjectivesTo determine whether sustained complete B cell (BC) depletion is associated with a better clinical response in RA patients long-term treated with RTX.MethodsRetrospective routine care study conducted in the Rheumatology department of Cochin hospital. We included consecutive patients fulfilling the ACR/EULAR 2010 classification criteria for RA hospitalized in 2021 for a new RTX infusion. All recruited patients had received at least 3 prior RTX infusions and had disease activity assessment (DAS28 and DAS28-CRP) and CD19 counts (Aquios, Beckman Coulter) available during each of the 4 last infusion visits. The primary endpoint was the course of DAS28 and DAS28-CRP, calculated the day of the last 4 infusion visits according to sustained complete (mean CD19 counts <18/µL) or incomplete (mean CD19 counts ≥18/µL) BC depletion. Secondary endpoints were the frequency of end-of-dose effect and patient self-reported RA flares at each infusion visit, as well as the course of pain/fatigue VAS, CRP and gammaglobulin levels according to complete or incomplete B cell depletion.ResultsWe included 126 patients (105 women, 83%) with a mean age of 64±12 years and a mean disease duration of 22± 5 years. Only 43 patients (34%) had maintained complete BC depletion during the last 4 infusions (mean CD19 counts 13±4/µL) (Figure 1A-B). Patients with incomplete BC depletion (n=83, mean CD19 counts: 77±73/µL, p<0.001) did not differ from those who maintained complete BC depletion in terms of age, gender, disease duration, structural damages and concomitant treatment.Patients with incomplete BC depletion had a higher frequency of rheumatoid factor (92% vs. 77%, p=0.018) and ACPA (84% vs. 72%, p=0.11);these patients had received RTX for a longer period (99±57 months vs. 69±47 months, p=0.003), with significantly higher number of infusions (14±7 vs. 12±6 infusions, p=0.037) and increased cumulative dose (10±6 g vs. 8±5 g, p=0.10) compared to patients with sustained complete BC depletion. On the other hand, their interval between 2 infusions was significantly longer (8±3 months vs. 6±1 months, p<0.001).The course of DAS28 and DAS28-CRP during the last 4 infusions was not different between the 2 groups (Figures 1C-D). The mean DAS28 and DAS28-CRP calculated at the time of last 4 infusion visits did not differ between patients with incomplete or sustained complete BC depletion (DAS28: 2.71±1.06 vs. 3.01±1.10, p=0.33 and DAS28-CRP: 2.53±0.88 vs. 2.88±0.84, p=0.095). The frequency of an end-of-dose effect and self-reported flares was similar between the 2 groups, as well as the evaluation of pain VAS, asthenia VAS, CRP and gammaglobulin levels (Figures 1E-H).ConclusionMaintaining complete BC depletion is not a therapeutic target to achieve in RA patients in long-term maintenance therapy with RTX. These results show that it is possible to space out RTX infusions to 8 months without loss of clinical benefit, which remains identical to that of patients treated every 6 months with sustained BC depletion. This result may have clinical implications during the COVID-19 pandemic since the antibody response to SARS-CoV-2 vaccination is preferentially obtained in patients with detectable B cells [3].References[1]Vital EM et al. Arthritis Rheum 2011;63:603–8.[2]Dass S et al. Arthritis Rheum 2008;58(10):2993–2999.[3]Avouac et al, Rheumatology 2022Figure 1.Course of mean (±SD) CD19, DAS28, DAS28-CRP, pain and fatigue VAS, CRP and gammaglobulins at the last 4 RTX infusion visits according to sustained complete or incomplete B cell depletion (CBCD and IBCD respectively).[Figure omitted. See PDF]Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background: Rituximab (RTX) is associated with reduced humoral response to SARS-CoV-2 mRNA-based vaccine (1, 2). A recent study has shown that, despite their immunosuppression burden, kidney transplant recipients with previous exposure to SARS-CoV-2 showed a marked increase in antibody titer, even after a single dose of vaccine (3). Objectives: To describe the results of immunization after 1 to 3 doses of mRNA SARS-CoV-2 vaccine in RTX-treated patients with previous symptomatic COVID-19 infection. Methods: Observational prospective usual care study including consecutive patients with infammatory rheumatic diseases in maintenance therapy with RTX. All patients received a 1 to 3-dose regimen of mRNA-based COVID-19 vaccination (BNT162b2 Pfzer/BioNTech or mRNA-1273, Moderna). Serum IgG antibody levels against SARS-CoV-2 spike proteins were measured at the time of the new RTX infusion. The SARS-CoV-2 S1/S2 IgG immunoassay (DiaSorin) was used for the quantitative determination of antibodies to the receptor-binding domain of the viral spike (S) protein. Seropositivity was defned by anti-S antibodies >15 UA/mL. Results: We included 69 patients (60 females, mean age 60±13 years) on maintenance therapy with RTX including 13 with previous symptomatic COVID-19, all proven by RT-PCR (10 females, mean age 58±12 years) (Table 1). Sympto-maticCOVID-19 occurred between March 2020 and May 2021. The mean interval between the infection and vaccination was 8±3 months and the serological response was assessed after a mean of 74±58 days from the last dose of vaccination (3rd dose for 3 patients, 2nd dose for 6 patients and 1st dose for 4 patients). The 56 patients with no history of symptomatic COVID-19 infection all received 3 doses of vaccine and the serological response was assessed after a mean of 63±27 days from the 3rd dose of vaccination. The seropositivity rate was signifcantly higher in RTX-treated patients with previous symptomatic COVID-19 infection (11/13, 85% vs.15/56, 27%, p<0.001). Anti-S antibody titles were also markedly increased in patients with previous symptomatic COVID-19 infection (median 119 AU/mL, 95% CI 16-400 AU/mL vs. 3.80 AU/mL, 95% CI 3.80-4.81 AU/mL p<0.0001) (Figure 1). Antibody titles were not different according to the severity of previous COVID-19, the number of doses of vaccine, the underlying disease, and B-cell counts. Conclusion: RTX-treated patients with previous proven COVID-19 showed increased seropositivity and antibody titers after SARS-CoV-2 vaccination, even after a single-dose of vaccine. This response is strikingly different from that observed for SARS-CoV-2-naïve RTX treated patients who received 3 doses of SARS-CoV-2 mRNA-based vaccination. An 'antigen dose phenomenon' may account for these discrepancies. A potential clinical implication might be to increase antibody response with an additional dose of vaccine following an exposure to SARS-CoV-2 in RTX-treated patients with absent or insufficient postvaccination antibody response.
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Background: It is now well established that patients treated with rituximab (RTX) for auto-immune disease (AID) have a diminished antibody response to COVID-19 vaccines after two doses. Optimizing antibody response is a key objective in this population. To achieve this goal, a 3rd booster dose may be considered. Objectives: Focusing on the population of AID patients treated with RTX without any antibody response after two doses we sought to explore how these patients could respond to a 3rd dose and identify factors of response. Methods: We performed a French retrospective bicentric observational trial which is a follow up of previously published work (1). We included consecutive patients treated with RTX that were non-responders regarding their anti-Spike antibody (anti-S) status at least one month after the second dose of COVID-19 vaccination. Patients were included between March and October 2021. All patients then received a third dose according to local guidelines and had an anti-S measurement at least one month after the third dose. Some patients without response to a third dose had a fourth dose. Anti-S were measured in serum with various kits, but all results were in BAU/mL with upper quantifcation limit at 243. Patients with anti-S above 49 BAU/mL, which has been demonstrated to be the threshold associated with detectable neutralizing response were considered as responders (1). Results: 60 patients treated with RTX without response to 2 doses (Anti-S Ab < 49 BAU/mL) were included in the study. 9/60 (15%) patients responded to the 3rd vaccine dose with anti-S > 49BAU/ml. Responders and non-responders had similar demographic characteristics (Table 1). There was a positive correlation between anti-S Ab levels after dose 3 and time between 2nd and 3rd doses (r=0,41 p=0,001) (Figure 1). Nevertheless, the median time between 2nd and 3rd doses was numerically but not signifcantly higher in responders than in non-responders (129 vs 80 days, p=0.30). There was no correlation between anti-S levels after the third dose and the time between the last RTX infusion and the third vaccine dose. There was a trend towards more patients with methotrexate co-medication in the non-responder group 31/51 (61%) vs 3/9 (33%) in the responder group (p=0,15). Seven non-responder patients after the 3rd dose received a 4th dose and 4 (57%) responded. Conclusion: A third vaccine dose of COVID-19 vaccine leads to only 15% of response in previously non-responding RTX treated AID patients. A longer time between 2nd and 3rd doses might positively influences response to a 3rd COVID-19 vaccine. Finally exploratory fndings show that a fourth dose could be useful to obtain response non-responders.