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- Brink, M, et al.
(author)
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PULMONARY FIBROSIS IN EARLY RHEUMATOID ARTHRITIS IN RELATION TO GENETIC LOCI AND INDIVIDUAL ACPA SPECIFICITIES
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 203-204
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Conference paper (other academic/artistic)abstract
- Pulmonary manifestations in rheumatoid arthritis (RA) are common comorbidities but the underlying mechanisms are largely unknown. We found in a previous study 3 SNPs associated with pulmonary fibrosis (PF); rs35705950 (MUC5B), rs111521887 (TOLLIP), and rs2609255 (FAM13A) besides age, rheumatoid factor positivity and methotrexate treatment.ObjectivesTo evaluate for the added value of a multiplex of anti-citrullinated peptide antibodies (ACPA) for the development of pulmonary fibrosis (PF) in an inception cohort of RA patients.MethodsA total of 1184 patients with early RA were consecutively included and followed prospectively from the date of diagnosis (index date) until death or until 31 December 2016. The diagnosis of PF was based on high resolution tomography. The presence of 21 ACPA fine specificities were analysed in plasma sampled at index date, using a custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden). Data on both ACPA and genetic data was available for 841 RA patients, of whom 50 developed PF. Associations were analysed using logistic regression analysis and presented as the odds ratio (OR) with the 95% confidence interval (CI). Models were adjusted for sex, age, DAS28 and presence of RF at RA diagnosis, smoking ever, and HLA-SE and in a second step for the three SNPs (.rs35705950, rs111521887 and rs2609255), respectively.ResultsIn unadjusted analyses eight ACPA reactivities were found associated with PF development (p< 0.05-0.001). The number of ACPA reactivities was related to PF development, both in crude and adjusted models (p<0.05 for both). In models concomitantly adjusted for the three SNPs (rs35705950, rs111521887 and rs2609255) respectively, in addition to mentioned adjustments the number of ACPA reactivities (p<0.05 for all three nmodels), Vim60-75 (p<0.05, in all three models), Fibβ62–78 (72) (p<0.001-p<0.05) and F4-CIT-R (p<0.01-p<0.05) were all found significantly associated to PF development irrespective of the SNPs.ConclusionThe development of PF in an inception cohort of RA patients was associated both with risk genes and, independently of the risk genes, the presence of certain ACPA, and the number of ACPA reactivities.References[1]Jönsson E, et al. Pulmonary fibrosis in relation to genetic loci in an inception cohort of patients with early rheumatoid arthritis from northern Sweden. Rheumatology (Oxford). 2021 May 16:keab441. doi: 10.1093/rheumatology/keab441.AcknowledgementsI have no acknowledgements to declare. The staff and patients at the departments of rheumatology in northern Sweden.Disclosure of InterestsNone declared
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- Cerqueira, C., et al.
(author)
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Neutralisation of ACPA – A Way to Go?
- 2013
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72:S1, s. A68-A68
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Journal article (other academic/artistic)
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- Circiumaru, A, et al.
(author)
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SPECIFIC ACPA REACTIVITIES AND INFLAMMATORY BIOMARKERS ALONG WITH ULTRASOUND TENOSYNOVITIS ARE ASSOCIATED WITH ARTHRITIS ONSET IN A POPULATION AT RISK FOR RHEUMATOID ARTHRITIS
- 2020
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1247-1247
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Conference paper (other academic/artistic)abstract
- Anti-citrullinated protein antibodies (ACPA) are characteristic markers for rheumatoid arthritis (RA), developing years before disease onset. Early clinical and biological biomarkers could provide useful information on the onset of RA in predisposed individuals.Objectives:The aim of the study was to investigate whether ACPA along with inflammatory markers and musculoskeletal ultrasound changes could predict arthritis development in individuals at risk for RA.Methods:ACPA-positive individuals with musculoskeletal complaints were referred from primary care to a rheumatology clinic, recruited in the Risk-RA research program and followed-up for up to 3 years, between April 2014 and October 2019. All individuals lacked arthritis both at clinical examination by a trained rheumatologist and ultrasound assessment of hands and feet and any other symptomatic joints (according to EULAR-OMERACT definition). Blood samples were collected at inclusion and were analyzed for 15 ACPA fine specificities (by custom made peptide array), 92 inflammation-associated protein biomarkers (by multiplex immunoassay with Olink extension technology) and HLA-SE (DR low resolution kit). Statistical analysis used univariate and multivariate models with backwards selection and cox regression.Results:268 individuals with a median age of 48 (36-58) were recruited, out of which 212 (79%) were females. 75 (28%) developed arthritis within 11 months of follow-up while the median follow-up for those not developing arthritis was 21 months (14-28). Increased ACPA levels, shorter symptom duration and RF positivity were the main differences between individuals developing arthritis and those who did not. In univariate models, the presence of HLA-SE, specific ACPA reactivities, certain inflammatory markers and ultrasound-detected tenosynovitis were associated with arthritis development. In multivariate analysis the presence of anti-cit-fillagrin (HR 2.1 (95% CI 1.2-3.7, p 0.01), IL6 levels (HR 1.4 (95% CI 1.2-1.7, p 0.0001) and tenosynovitis (HR 2.9 (95% CI 1.7-5.0, p 0.0001) remained significant predictors for arthritis onset.Conclusion:Certain ACPA reactivities together with inflammatory markers and ultrasound-detected tenosynovitis predict arthritis development in predisposed individuals for developing RA.Disclosure of Interests:None declared
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- Frodlund, M., et al.
(author)
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Predictors Of Antibody Response To Covid-19 Vaccine In Rituximab Treated Patients With Inflammatory Rheumatic Diseases. A Swedish Nationwide Study (Covid19-Reuma)
- 2022
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 368-369
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Journal article (other academic/artistic)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
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| 9. |
- Frodlund, M., et al.
(author)
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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
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82, s. 533-533
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Journal article (other academic/artistic)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.
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- Gerlag, DM, et al.
(author)
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Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study
- 2019
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:2, s. 179-185
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Journal article (peer-reviewed)abstract
- We explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.MethodsIndividuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.ResultsEighty-one individuals received treatment and were followed up for a mean of 29.0 (0–54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.ConclusionsA single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.
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