Clinical and humoral response after SARS-CoV-2 breakthrough infection in patients receiving immunosuppressant therapy.

BACKGROUND: Despite impaired humoral response in patients treated with immunosuppressants (ISPs), recent studies found similar severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection compared to controls. One potential explanation is the rapid generation of humoral response on infection, but evidence is lacking. OBJECTIVES: We investigated the longitudinal dynamics of the SARS-CoV-2 antibody repertoire after SARS-CoV-2 delta and omicron breakthrough infection in patients with immune-mediated inflammatory diseases (IMIDs) receiving ISP therapy and controls. METHODS: As a prospective substudy of the national Target-to-B! (T2B!) consortium, we included IMID patients receiving ISPs therapy and controls who reported SARS-CoV-2 breakthrough infection between July 1, 2021, and April 1, 2022. To get an impression of the dynamics of the antibody repertoire, 3 antibody titers of wild-type RBD, wild-type S, and omicron RBD were measured at 4 time points after SARS-CoV-2 breakthrough infection. RESULTS: We included 302 IMID patients receiving ISPs and 178 controls. Antibody titers increased up to 28 days after breakthrough infection in both groups. However, in IMID patients receiving therapy with anti-CD20 and sphingosine-1 phosphate receptor modulators, antibody titers were considerably lower compared to controls. In the anti-TNF group, we observed slightly lower antibody titers in the early stages and a faster decline of antibodies after infection compared to controls. Breakthrough infections were mostly mild, and hospitalization was required in less than 1% of cases. CONCLUSIONS: Most ISPs do not influence the dynamics of the SARS-CoV-2 antibody repertoire and exhibit a rapid recall response with cross-reactive antibody clones toward new virus variants. However, in patients treated with anti-CD20 therapy or sphingosine-1 phosphate receptor modulators, the dynamics were greatly impaired, and to a lesser extent in those who received anti-TNF. Nevertheless, only a few severe breakthrough cases were reported.

Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after mRNA vaccination.

BACKGROUND: The noninflammatory immunoglobulin G4 (IgG4) is linked to tolerance and is unique to humans. Although poorly understood, prolonged antigenic stimulation and IL-4-signaling along the T helper 2-axis may be instrumental in IgG4 class switching. Recently, repeated SARS-CoV-2 mRNA vaccination has been linked to IgG4 skewing. Although widely used immunosuppressive drugs have been shown to only moderately affect humoral responses to SARS-CoV-2 mRNA vaccination, the effect on IgG4 switching has not been investigated. METHODS: Here we study the impact of such immunosuppressive drugs, including the IL-4 receptor-blocking antibody dupilumab, on IgG4 skewing upon repeated SARS-CoV-2 mRNA vaccination. Receptor-binding domain (RBD) specific antibody responses were longitudinally measured in 600 individuals, including patients with immune-mediated inflammatory diseases treated with a TNF inhibitor (TNFi) and/or methotrexate (MTX), dupilumab, and healthy/untreated controls, after repeated mRNA vaccination. RESULTS: We observed a substantial increase in the proportion of RBD-specific IgG4 antibodies (median 21%) in healthy/untreated controls after third vaccination. This IgG4 skewing was profoundly reduced in dupilumab-treated patients (<1%). Unexpectedly, an equally strong suppression of IgG4 skewing was observed in TNFi-treated patients (<1%), whereas MTX caused a modest reduction (7%). RBD-specific total IgG levels were hardly affected by these immunosuppressive drugs. Minimal skewing was observed, when primary vaccination was adenoviral vector-based. CONCLUSIONS: Our results imply a critical role for IL-4/IL-13 as well as TNF in vivo IgG4 class switching. These novel findings advance our understanding of IgG4 class switch dynamics, and may benefit humoral tolerance induction strategies, treatment of IgG4 pathologies and mRNA vaccine optimization.

T cell activation markers CD38 and HLA-DR indicative of non-seroconversion in anti-CD20-treated patients with multiple sclerosis following SARS-CoV-2 mRNA vaccination.

BACKGROUND: Messenger RNA (mRNA) vaccines provide robust protection against SARS-CoV-2 in healthy individuals. However, immunity after vaccination of patients with multiple sclerosis (MS) treated with ocrelizumab (OCR), a B cell-depleting anti-CD20 monoclonal antibody, is not yet fully understood. METHODS: In this study, deep immune profiling techniques were employed to investigate the immune response induced by SARS-CoV-2 mRNA vaccines in untreated patients with MS (n=21), OCR-treated patients with MS (n=57) and healthy individuals (n=30). RESULTS: Among OCR-treated patients with MS, 63% did not produce detectable levels of antibodies (non-seroconverted), and those who did have lower spike receptor-binding domain-specific IgG responses compared with healthy individuals and untreated patients with MS. Before vaccination, no discernible immunological differences were observed between non-seroconverted and seroconverted OCR-treated patients with MS. However, non-seroconverted patients received overall more OCR infusions, had shorter intervals since their last OCR infusion and displayed higher OCR serum concentrations at the time of their initial vaccination. Following two vaccinations, non-seroconverted patients displayed smaller B cell compartments but instead exhibited more robust activation of general CD4+ and CD8+ T cell compartments, as indicated by upregulation of CD38 and HLA-DR surface expression, when compared with seroconverted patients. CONCLUSION: These findings highlight the importance of optimising treatment regimens when scheduling SARS-CoV-2 vaccination for OCR-treated patients with MS to maximise their humoral and cellular immune responses. This study provides valuable insights for optimising vaccination strategies in OCR-treated patients with MS, including the identification of CD38 and HLA-DR as potential markers to explore vaccine efficacy in non-seroconverting OCR-treated patients with MS.

Tocilizumab Dose Tapering Based on a Model-Based Algorithm is Feasible in Clinical Practice: A Short Communication.

BACKGROUND: Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure-response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients. METHODS: A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4-6 mg/L after 20 weeks of dose tapering. RESULTS: Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4-6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups. CONCLUSIONS: This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity.

BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Risk factors associated with short-term adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases.

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.

EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome.

OBJECTIVE: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). METHODS: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion. RESULTS: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering. CONCLUSION: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases.

Breakthrough infections with the SARS-CoV-2 omicron (B.1.1.529) variant in patients with immune-mediated inflammatory diseases.

OBJECTIVES: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. METHODS: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. RESULTS: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. CONCLUSIONS: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections.

Time to talk to adults with rheumatic diseases about herpes zoster vaccination.

The 2019 European Alliance of Associations for Rheumatology (EULAR) recommendations on herpes zoster vaccination for adult patients with rheumatic immune-mediated inflammatory diseases stated that these patients are at increased risk of herpes zoster compared with the general population. However, these recommendations lack clarity and specificity and are cautiously phrased, which might cause physicians to underestimate the importance of herpes zoster vaccination for these patients, potentially resulting in suboptimal protection. Since the formulation of the 2019 EULAR guidelines, new data on herpes zoster in patients with immune-mediated inflammatory diseases have been published. Moreover, a recombinant herpes zoster vaccine (Shingrix) has become available that can be given to these patients in a more accessible manner than the original live-attenuated vaccine (Zostavax). Here, we evaluate existing evidence on risk factors for herpes zoster and the safety and efficacy of the recombinant vaccine in patients with rheumatic immune-mediated inflammatory diseases and discuss the necessity of herpes zoster vaccination for these patients.

Work participation and the COVID-19 pandemic: an observational study in people with inflammatory rheumatic diseases and population controls.

Objective: During the coronavirus disease 2019 (COVID-19) crisis, people with inflammatory rheumatic diseases (iRDs) might have been more vulnerable for adverse work outcomes (AWOs) and restrictions in work ability and work performance. Our objectives were to compare AWOs during the pandemic and current work ability between iRD patients and controls, understand which patients are most vulnerable for these outcomes and (3) explore the role of work characteristics on work performance while working remotely. Methods: Patients and population controls in a Dutch COVID-19 cohort study provided information in March 2022 on work participation in March 2020 (pre-pandemic, retrospective) and March 2022 (current). AWOs comprised withdrawal from paid work, working hours reduction or long-term sick leave. Multivariable logistic/linear regression analyses compared outcomes (AWOs/work ability) between groups (patients/controls) and within patients. Results: Of the pre-pandemic working participants, 227/977 (23%) patients and 79/430 (18%) controls experienced AWOs following pandemic onset. A minority of AWOs (15%) were attributed to COVID-19. Patients were more likely to experience any-cause AWOs (odds ratio range 1.63-3.34) but not COVID-related AWOs, with female patients and patients with comorbidities or physically demanding jobs being most vulnerable. Current work ability was lower in female patients compared with controls [ß = -0.66 (95% CI -0.92 to -0.40)]. In both groups, when working remotely, care for children and absence of colleagues had varying effects on work performance (positive 19% and 24%, negative 34% and 57%, respectively), while employer support and reduced commuting had mainly positive effects (83% and 86%, respectively). Conclusion: During the pandemic, people with iRDs remained at increased risk of AWOs. COVID-related AWOs, however, were infrequent.

Patient-perspective and feasibility of home finger-prick testing to complement and facilitate large-scale research in rheumatology.

BACKGROUND: During the COVID-19 pandemic, we developed a digital research platform to longitudinally investigate COVID-19-related outcomes in patients with rheumatic diseases and healthy controls. We used home finger-prick testing in order to collect serum samples remotely and increase the overall efficiency of the platform. The aim of the present study was to evaluate the success rate of the finger prick and patients' perspective towards the finger prick. METHODS: Serum samples were collected up to five times during follow-up, either via a venepuncture at the research institute or a finger prick from participants' home. Participants were asked to complete a digital evaluation questionnaire of the finger prick after their attempts. RESULTS: A total of 2135 patients and 899 controls performed at least one finger prick and were included in this study. The first finger prick was successfully done by 92% (95% CI: 90% to 93%) of patients, 94% (95% CI: 92% to 95%) of controls, 93% (95% CI: 92% to 94%) of all participants aged ≤70 years and 89% (95% CI: 86% to 92%) of all participants aged >70 years. Sex did not impact these success rates. Repeated failure occurred in 11/439 (0.8%) patients and 4/712 (0.6%) controls. Both patients and controls were less willing to perform a finger prick for individual healthcare compared with scientific research. CONCLUSION: The vast majority of participants, among which elderly and patients with rheumatic diseases, were able to successfully draw the required amount of blood for serological analyses. This shows that finger-prick testing is suitable for a high-throughput implementation to monitor patients remotely.

Longitudinal rheumatoid factor autoantibody responses after SARS-CoV-2 vaccination or infection.

Background: Rheumatoid factors (RFs) are autoantibodies that target the Fc region of IgG, and are found in patients with rheumatic diseases as well as in the healthy population. Many studies suggest that an immune trigger may (transiently) elicit RF responses. However, discrepancies between different studies make it difficult to determine if and to which degree RF reactivity can be triggered by vaccination or infection. Objective: We quantitatively explored longitudinal RF responses after SARS-CoV-2 vaccination and infection in a well-defined, large cohort using a dual ELISA method that differentiates between true RF reactivity and background IgM reactivity. In addition, we reviewed existing literature on RF responses after vaccination and infection. Methods: 151 healthy participants and 30 RA patients were included to measure IgM-RF reactivity before and after SARS-CoV-2 vaccinations by ELISA. Additionally, IgM-RF responses after a SARS-CoV-2 breakthrough infection were studied in 51 healthy participants. Results: Published prevalence studies in subjects after infection report up to 85% IgM-RF seropositivity. However, seroconversion studies (both infection and vaccination) report much lower incidences of 2-33%, with a trend of lower percentages observed in larger studies. In the current study, SARS-CoV-2 vaccination triggered low-level IgM-RF responses in 5.5% (8/151) of cases, of which 1.5% (2/151) with a level above 10 AU/mL. Breakthrough infection was accompanied by development of an IgM-RF response in 2% (1/51) of cases. Conclusion: Our study indicates that de novo RF induction following vaccination or infection is an uncommon event, which does not lead to RF epitope spreading.

Methotrexate treatment hampers induction of vaccine-specific CD4 T cell responses in patients with IMID.

OBJECTIVES: Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination. METHODS: In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3-6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells. RESULTS: Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients. CONCLUSION: Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses. TRIAL REGISTRATION NUMBER: NL8900.

Cardiovascular disease risk in patients with inflammatory arthritis nowadays still substantially elevated.

OBJECTIVES: This study aims to assess current cardiovascular disease risk and prevalence of risk factors in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (SpA). METHODS: 2050 consecutive patients with inflammatory arthritis (IA) and 939 controls were included, with 1308 patients with RA, 356 patients with PsA and 386 patients with SpA. In a prospective cohort setting, questionnaires regarding previous cardiovascular events and risk factors were used to assess cardiovascular risk and prevalence in patients with IA by calculating ORs using logistic regression models. RESULTS: 'Traditional' cardiovascular (CV) risk factors were significantly elevated in patients with IA compared with controls. Cardiovascular disease (CVD) ORs were increased in patients with RA and PsA compared with controls, 1.61 (95% CI: 1.04 to 2.48) and 2.12 (95% CI: 1.23 to 3.66), respectively, and a trend towards increased odds was observed in patients with SpA (OR 1.43; 95% CI: 0.79 to 2.59). After adjusting for traditional risk factors, CV risk was not increased in patients with RA (OR; 0.95, 95% CI: 0.58 to 1.55), PsA (OR 1.19; 95% CI: 0.64 to 2.22) and SpA (OR; 0.91, 95% CI: 0.47 to 1.77). CONCLUSION: CVD is currently still more prevalent in patients with IA compared with healthy controls and, more importantly, this elevated risk is highly influenced by an increased prevalence of 'traditional' CV risk factors. More attention to, as well as improvements in, identification and treatment of 'traditional' risk factors, need to be made for not only RA, but other IA conditions as well.

Post-COVID condition in patients with inflammatory rheumatic diseases: a prospective cohort study in the Netherlands.

Background: Studies on long-term consequences of COVID-19, commonly referred to as post-COVID condition, in patients with inflammatory rheumatic diseases are scarce and inconclusive. Furthermore, classifying patients with inflammatory rheumatic diseases as having post-COVID condition is complicated because of overlapping symptoms. Therefore, we investigated the risk of post-COVID condition and time until recovery, and compared the prevalence of symptoms seen in post-COVID condition, between patients with inflammatory rheumatic diseases and healthy controls, with and without a history of COVID-19. Methods: In this substudy we used data from an ongoing prospective cohort study in the Netherlands. All adult patients with inflammatory rheumatic diseases from the Amsterdam Rheumatology and Immunology Center in Amsterdam, the Netherlands, were invited to participate in the study between April 26, 2020, and March 1, 2021. All patients were asked, but not obliged, to recruit their own control participant of the same sex, of comparable age (< 5 years), and without an inflammatory rheumatic disease. Demographic and clinical data, including data on the occurrence of SARS-CoV-2 infections, were collected via online questionnaires. On March 10, 2022, all study participants received a questionnaire on the occurrence, onset, severity, and duration of persistent symptoms during the first 2 years of the COVID-19 pandemic, independent of their history of SARS-CoV-2 infection. Additionally, we prospectively monitored a subset of participants who had a PCR or antigen confirmed SARS-CoV-2 infection in the 2-month period surrounding the questionnaire in order to assess COVID-19 sequelae. In line with WHO guidelines, post-COVID condition was defined as persistent symptoms that lasted at least 8 weeks, started after the onset and within 3 months of a PCR or antigen-confirmed SARS-CoV-2 infection, and could not be explained by an alternative diagnosis. Statistical analyses included descriptive statistics, logistic regression analyses, logistic-based causal mediation analyses, and Kaplan-Meier survival analyses for time until recovery from post-COVID condition. In exploratory analyses, E-values were calculated to investigate unmeasured confounding. Findings: A total of 1974 patients with inflammatory rheumatic disease (1268 [64%] women and 706 [36%] men; mean age 59 years [SD 13]) and 733 healthy controls (495 [68%] women and 238 [32%] men; mean age 59 years [12]) participated. 468 (24%) of 1974 patients with inflammatory rheumatic disease and 218 (30%) of 733 healthy controls had a recent SARS-CoV-2 omicron infection. Of those, 365 (78%) of 468 patients with inflammatory rheumatic disease and 172 (79%) of 218 healthy controls completed the prospective follow-up COVID-19 sequelae questionnaires. More patients than controls fulfilled post-COVID condition criteria: 77 (21%) of 365 versus 23 (13%) of 172 (odds ratio [OR] 1·73 [95% CI 1·04-2·87]; p=0·033). The OR was attenuated after adjusting for potential confounders (adjusted OR 1·53 [95% CI 0·90-2·59]; p=0·12). Among those without a history of COVID-19, patients with inflammatory diseases were more likely to report persistent symptoms consistent with post-COVID condition than were healthy controls (OR 2·52 [95% CI 1·92-3·32]; p<0·0001). This OR exceeded the calculated E-values of 1·74 and 1·96. Recovery time from post-COVID condition was similar for patients and controls (p=0·17). Fatigue and loss of fitness were the most frequently reported symptoms in both patients with inflammatory rheumatic disease and healthy controls with post-COVID condition. Interpretation: Post-COVID condition after SARS-CoV-2 omicron infections was higher in patients with inflammatory rheumatic disease than in healthy controls based on WHO classification guidelines. However, because more patients with inflammatory rheumatic disease than healthy controls without a history of COVID-19 reported symptoms that are commonly used to define a post-COVID condition during the first 2 years of the pandemic, it is likely that the observed difference in post-COVID condition between patients and controls might in part be explained by clinical manifestations in the context of underlying rheumatic diseases. This highlights the limitations of applying current criteria for post-COVID condition in patients with inflammatory rheumatic disease, and suggests it might be appropriate for physicians to keep a nuanced attitude when communicating the long-term consequences of COVID-19. Funding: ZonMw (the Netherlands organization for Health Research and Development) and Reade foundation.

Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273.

Background: Patients affected by different types of autoimmune diseases, including common conditions such as multiple sclerosis (MS) and rheumatoid arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants. Methods: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. Results: OCR-treated MS patients exhibit a preserved recall response of CD8+ T central memory cells following first vaccination compared to HCs and a similar CD4+ circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4+ and CD8+ T cells. Conclusions: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8+ T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients. Funding: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871).

Antibody development and disease severity of COVID-19 in non-immunised patients with rheumatic immune-mediated inflammatory diseases: data from a prospective cohort study.

BACKGROUND: Research on the disease severity of COVID-19 in patients with rheumatic immune-mediated inflammatory diseases (IMIDs) has been inconclusive, and long-term prospective data on the development of SARS-CoV-2 antibodies in these patients are lacking. METHODS: Adult patients with rheumatic IMIDs from the Amsterdam Rheumatology and Immunology Center, Amsterdam were invited to participate. All patients were asked to recruit their own sex-matched and age-matched control subject. Clinical data were collected via online questionnaires (at baseline, and after 1-4 and 5-9 months of follow-up). Serum samples were collected twice and analysed for the presence of SARS-CoV-2-specific antibodies. Subsequently, IgG titres were quantified in samples with a positive test result. FINDINGS: In total, 3080 consecutive patients and 1102 controls with comparable age and sex distribution were included for analyses. Patients were more frequently hospitalised compared with controls when infected with SARS-CoV-2; 7% vs 0.7% (adjusted OR: 7.33, 95% CI: 0.96 to 55.77). Only treatment with B-cell targeting therapy was independently associated with an increased risk of COVID-19-related hospitalisation (adjusted OR: 14.62, 95% CI: 2.31 to 92.39). IgG antibody titres were higher in hospitalised compared with non-hospitalised patients, and slowly declined with time in similar patterns for patients in all treatment subgroups and controls. INTERPRETATION: We observed that patients with rheumatic IMIDs, especially those treated with B-cell targeting therapy, were more likely to be hospitalised when infected with SARS-CoV-2. Treatment with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs other than B-cell targeting agents is unlikely to have negative effects on the development of long-lasting humoral immunity against SARS-CoV-2.

Longitudinal T-Cell Responses After a Third SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis on Ocrelizumab or Fingolimod.

OBJECTIVES: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod. METHODS: This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2-specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated. RESULTS: In ocrelizumab-treated patients (N = 24), IFN-γ-producing SARS-CoV-2-specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2-specific T cells were detected after second (N = 12) and third (N = 9) vaccinations. DISCUSSION: In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination.