| 1. |
- Frodlund, M., et al.
(författare)
-
Predictors Of Antibody Response To Covid-19 Vaccine In Rituximab Treated Patients With Inflammatory Rheumatic Diseases. A Swedish Nationwide Study (Covid19-Reuma)
- 2022
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 368-369
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In line with other reports, our group showed that patients treated with rituximab had significant impaired antibody response compared to patients treated with other biologic and targeted and synthetic disease modifying anti-rheumatic drugs (csDMARD).ObjectivesTo investigate predictors of response to COVID-19 vaccination (2 doses of mRNA vaccines, 2 doses of virus vector vaccines or combinations of these) in patients with inflammatory rheumatic diseases (IRD) treated with rituximab and controls.MethodsAntibody levels to three antigens: Spike protein full length, Spike S1 and Nucleocapsid C-terminal fragment (to confirm previous COVID-19 infection) were measured in sera collected before vaccination and 2-12 weeks after the second vaccine using a multiplex bead-based serology assay. The antigen-specific cut-off was defined as the median fluorescence intensity signal plus 6x standard deviations across 12 pre-pandemic controls. A good vaccine response was defined as having antibodies over the cut-off level for both spike antigens. Proportion (%) responders was compared between patients and controls (Chi2 test).Patients with IRD receiving last rituximab treatment within a mean (range) 193 (23-501) days before first vaccination participated. Individuals without IRD served as a control group. Predictors of a good vaccine response were explored using multivariate logistic regression analysis adjusted for age, sex, disease duration, diagnosis (systemic vasculitis/RA/JIA/other), concomitant csDMARD, rituximab dose and prednisolone dose. Hazard ratio (chanse) of a good antibody response in relation to time between the last rituximab treatment and vaccination was studied by Kaplan-Meier survival analysis.ResultsIn total, 145 patients receiving rituximab and 61 controls were inclyded. Of these, 82 received rituximab as monotherapy (67% women; mean age 66 years, mean disease duration 13 years; 33% had RA/JIA and 60% vasculitis) and 63 received rituximab+csDMARD (62% women; mean age 66 years; mean disease duration 17 years; 76% had RA/JIA and 10 % vasculitis). Controls (n=61) were 74% women and mean age 49 years. Compared to controls, rituximab patients had lower antibody levels for both spike proteins (p<0.001). Proportion (%) responders among patients receiving rituximab as monotherapy (40.2%) and rituximab+DMARDs (25.4%) was significantly lower than in controls (98.4%) (p<0.001, Chi2). Higher age, concomitant csDMARD at vaccination and shorter time from last rituximab treatment predicted impaired antibody response (multivariate logistic regression model) (Table 1). Longer time between the last rituximab course and vaccination was associated with better antibody response (Figure 1).Table 1.Predictors of good antibody response to two doses of COVID-19 vaccine defined as antibodies over the cut-off level for both spike antigensBp-valueOR95% CIAge at vaccination (years)-0.040.0090.960.93-0.99Sex (male/female)-9.550.2090.580.24-1.36csDMARD at vaccination (yes/no)-1.080.0260.340.13-0.88Prednisolone (mg/dag)-0.100.1030.900.80-1.02Rituximab dos (1000 mg vs 500 mg)-0.010.3700.990.99-1.00Time between the last rituximab and vaccination (months)0.200.0011.311.11-1.55Diagnosis at vaccination (systemic vasculitis vs others)-0.510.3150.600.21-1.64Figure 1.The chance of good antibody response following two doses of COVID-19 vaccine in relation to time between the last rituximab course and vaccination.ConclusionPatients with IRD getting vaccinated with two doses of COVID19 vaccine during the treatment with rituximab have the ability to develop antibody response although the response is impaired. For each month passed after the last rituximab course, the chance of good antibody response increases with 30%. Younger patients receiving rituximab as monotherapy and vaccinated preferably several months after the last rituximab treatment have the highest chance of achieving a good antibody response.AcknowledgementsUnrestricted research grants have been received from Roche and starting grants from The Swedish Rheumatism AssociationDisclosure of InterestsMartina Frodlund: None declared, Katerina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer., Anna Södergren: None declared, Eva Klingberg: None declared, Monika Hansson: None declared, Elisa Pin: None declared, Sophie Olsson: None declared, Anders Bengtsson: None declared, Lars Klareskog Grant/research support from: has eceived research grants from Pfizer, BMS, Affibody, Sonoma Biotherapeutics, Meliha C Kapetanovic Consultant of: have received consultancy fees from Abbvie, Pfizer and GSK, Grant/research support from: have received unrestricted research grants from Roche and Pfizer
|
|
| 2. |
|
|
| 3. |
- Frodlund, M., et al.
(författare)
-
The impact of immunomodulating treatment on the serological immunogenicity following three doses of covid-19 vaccine and persistence of immunogenicity of two vaccine doses in patients with inflammatory rheumatic diseases - a swedish study (covid19-reuma)
- 2023
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82, s. 533-533
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background Data on serological immunity after three doses and the long-term immunogenicity (persistence) of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with different immunomodulating drugs are still limited.Objectives To elucidate if 1) a third dose COVID-19 vaccine improves antibody responses, compared to two doses, in patients with IRD treated with biologic or targeted synthetic DMARD (b/tsDMARDs) treatment given as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) compared to controls, and 2) the persistence of antibody response after two doses of COVID-19 vaccine in IRD patients.Methods Antibody levels to two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confirm previous COVID-19 infection) were measured in serum samples collected 2-12 and 21-40 weeks after the second vaccine dose and 2-12 weeks after the third dose using a multiplex bead-based serology assay. A sufficient antibody response (seropositivity) was defined as having antibodies over the cut-off level for both spike antigens (1). WT (wild type) anti-Spike IgG and omicron BA.1 and BA.2 variants were measured. Patients with IRD receiving immunomodulating treatment, regularly followed at a rheumatology department and a group of controls were recruited from five Swedish region.Results In total, 323 of 414 patients with IRD and 36 controls who received three vaccine doses participated in this part of the study. Following treatment groups were included: rituximab (n=118; 68% female; mean age 67 years), abatacept (n=18; 72% female; mean age 64 years), IL6r inhibitors (n=60; 73% female; mean age 64 years), JAK-inhibitors (n=44; 80% female, mean age 52 years), TNF-inhibitors (n=59; 70% female; mean age 47 years;), IL12/23/17 inhibitors (n=24; 46% female; mean age 54 years) and controls (n=36; 75% female, mean age 51 years). b/ts DMARD treatment was given as monotherapy or in combination with csDMARD, methotrexate (MTX) being the most frequently used csDMARD (32.5%). Compared to results after two vaccine doses, proportion (%) of seropositivity after three vaccine doses increased significantly in groups rituximab +/- DMARD (p=0.003 and p=0.004, respectively), IL6r inhibitors +DMARD (p=0.02), and abatacept+DMARD (p=0.01). However, the proportion of seropositivity after three vaccine doses was still significantly lower in rituximab treated patients (52%) compared to other treatment groups or controls (p<0.001) (Figure 1A/B). Antibody response to WT, omicron sBA.1 and sBA.2 showed similar pattern with the lowest levels among patients treated with rituximab.When antibody response was compared between 2-12 weeks and 21-40 weeks after second dose, the proportion of seropositive rituximab treated patients decreased from 34.9 % to 32.6%. All patients with JAK inhibitors and with JAK-inhibitors and IL6r-inhibitors seropositive 21-40 weeks after the second vaccine dose. Patients treated with other bDMARDs were not included in this analysis due to limited number participants.Conclusion In this Swedish study including IRD patients receiving different b/t DMARDs, a sufficient immunogenicity of the third dose of COVID-19 vaccine was observed in all treatments with exception for rituximab. However, the increased proportion of seropositivity after the third COVID-19 vaccine doses in rituximab and other patients with insufficient response to two doses including response to the omicron variants, supports the current recommendations on additional booster doses. The immunogenicity of two vaccine doses was preserved to 40 weeks in majority of patients treated with different immunomodulating treatment with exception for rituximab.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Frodlund, M, et al.
(författare)
-
THE IMPACT OF IMMUNOMODULATING TREATMENT ON THE IMMUNOGENICITY OF COVID-19 VACCINES IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY RHEUMATIC DISEASES COMPARED TO HEALTHY CONTROLS. A SWEDISH NATIONWIDE STUDY (COVID19-REUMA)
- 2022
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 113-114
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Initial studies on the immunogenicity of COVID-19 vaccines in patients with immune-mediated inflammatory rheumatic diseases (IRD) reported diminished antibody response in general, and particularly when treated with rituximab or abatacept (1). Additional data are needed, especially for patients with IRD and immunomodulatory treatments.ObjectivesTo elucidate the antibody response after two doses of COVID-19 vaccine in patients with IRD treated with biologic or targeted synthetic disease modifying anti-rheumatic drugs (b/ts DMARDs) as monotherapy or combined with conventional synthetic DMARDS (csDMARDs).MethodsAntibodies against two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confirm previously COVID-19 infection) were measured in serum obtained before and after the second vaccination using a multiplex bead-based serology assay (2). Patients with IRD receiving immunomodulating treatment, followed at a rheumatology department and healthy individuals (controls) were recruited from five Swedish regions. Antibody positivity was classified as the signal passing an antigen specific cutoff based on the mean intensity signal of 12 selected negative pre-pandemic controls plus 6SD for Spike/S1 and 12SD for Nucleocapsid-C. Good vaccine response was defined as having antibodies over cut-off level for both spike antigens. Percentage of responders in each treatment group was compared to controls (Chi2 test). Predictors of antibody response were determined using logistic regression analysis.ResultsIn total, 414 patients (320 RA/JIA/psoriatic arthritis/axial spondylarthritis, 60 systemic vasculitis and 32 other IRD) and 61 controls participated. Patients receiving rituximab (n=145; 65% female; mean age 65years), abatacept (n=21; 77% female; mean age 66 years), IL6 inhibitors (n=77; 74% female; mean age 64years), JAK-inhibitors (n=58; 75% female, mean age 53years), TNF-inhibitors (n=68; 66% female; mean age 44years;), IL17 inhibitors (n=42; 54% female; mean age 44years) and controls (n=61; 74% female, mean age 49years) were studied. Patients receiving IL6 inhibitor (81.0%), abatacept (43.8%) or rituximab (33.8%) had a significantly lower antibody response rate compared to controls (98.4%), further pronounced if combined with csDMARD (p<0.001) (Figure 1). In the adjusted logistic regression analysis, higher age, rituximab, abatacept, concomitant csDMARD but not IL6 inhibitors, concomitant prednisolone, or a vasculitis diagnosis, remained significant predictors of antibody response (Table 1). All vaccines were well tolerated. 14 (3.4%) patients reported an increased activity in their IRD following vaccination.ConclusionIn this nationwide study including IRD patients receiving b/ts DMARDs a decreased immunogenicity of COVID-19 vaccines was observed in patients receiving rituximab, abatacept and to some extent IL-6 inhibitors. Concomitant csDMARD gave further attenuation. Patients on rituximab and abatacept should be prioritized for booster doses of COVID19 vaccine.References[1]Jena, et al. Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: Systematic rev./meta-analysis. Autoim. Rev: 2021;102927[2]Hober, et al. Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serol. C-19 assay. Clin Transl Im. 2021;10(7): e1312Table 1.Predictors of antibody response to COVID-19 vaccineRituximab-1.799<0.0010.170.07-0.42Abatacept-1.9710.0010.140.04-0.45IL6 inhibitor0.0230.9651.020.36-2.94Age (years)-0.0810.0000.920.89-0.96csDMARD-1.1270.0020.320.16-0.66Prednisolone (mg/day)-0.0640.2060.940.85-1.04Frequency (%) of individuals with good antibody response to COVID-19 vaccineAcknowledgementsUnrestricted research grants have been received från Roche and starting grants from the Swedish Rheumatism AssociationDisclosure of InterestsMartina Frodlund Consultant of: Consultancy fees from AstraZeneca and GSK, Katerina Chatzidionysiou Consultant of: Consultancy fees from Eli Lilly, AbbVie and Pfizer, Anna Södergren: None declared, Eva Klingberg: None declared, Anders Bengtsson: None declared, Lars Klareskog Grant/research support from: Research grants from Pfizer, BMS, Affibody, Sonoma Biotherapeutics, Meliha C Kapetanovic: None declared
|
|
| 7. |
|
|
| 8. |
- Linge, Petrus, et al.
(författare)
-
NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus
- 2020
-
Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 79:2, s. 254-261
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47phox, reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE. Methods: Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings. Results: Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-β2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-β2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087). Conclusions: The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.
|
|
| 9. |
|
|
| 10. |
|
|
